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66 publications mentioning mmu-mir-499

Open access articles that are associated with the species Mus musculus and mention the gene name mir-499. Click the [+] symbols to view sentences that include the gene name, or the word cloud on the right for a summary.

1
[+] score: 260
Other miRNAs from this paper: mmu-mir-208a, rno-mir-208a, rno-mir-499
By gain- and loss-of-function methods, including stable overexpression of miR-499 and Sox6 and transient down-regulation of miR-499 and Sox6, we demonstrate that Sox6, as a repressor of cyclin D1, arrests cardiomyocyte proliferation and facilitates cell cycle exit; miR-499 on the other hand downregulates the expression of its target protein, Sox6, to an appropriate level so as to prevent cardiomyocyte apoptosis. [score:13]
During skeletal muscle atrophy, increased expression of Sox6 was associated with down-regulation of miR-499 [18]; in neonatal rat cardiomyocytes, Sox6 mRNA expression was significantly reduced after miR-499 overexpression [18, 19]. [score:10]
As miRNAs usually show pronounced spatial and temporal expression patterns, we analyzed the time course of miR-499 expression and the expression of its target gene Sox6 during cardiomyocyte differentiation in the P19CL6 in vitro differentiation system. [score:9]
Sox6 overexpression inhibited cell proliferation, which means that it might be required for the terminal differentiation of cells; at the same time, overexpression of Sox6 resulted in increased cell apoptosis, which was also observed in the case of miR-499 knock-down. [score:8]
The results demonstrated that although miR-499 was overexpressed in these cells, the overexpression of Sox6 could inhibit the proliferation induced by miR-499, and the proliferation rate returned to normal. [score:7]
Two groups [7, 16] have documented that miR-499 overexpression reduces proliferation and enhances differentiation of cardiac stem cells or cardiomyocyte progenitor cells; it increases the expression of cardiac troponin T, α-cardiac actinin, and MLC-2v or the expression of Nkx-2.5 and GATA4. [score:7]
The expression profile of Sox6 indicated that Sox6 was not detected until day 8 of induction, and that its expression reached the highest value on day 10 (Figure 4E ), by which time miR-499 expression started to increase (Figure 1C ). [score:7]
In addition, the effects of anti-499 were further examined by: miR-499 knock-down resulted in increased Sox6 expression, thus reduced cyclin D1 expression (Figure 7D ). [score:6]
Sox6 was identified as a direct target of miR-499 and its expression was detected from day 8 or day 10 of cardiac differentiation of P19CL6 cells. [score:6]
miR-499 is an miRNA that is abundantly found in cardiac cells and is essentially undetectable in human cardiac stem cells (hCSCs) or human embryonic stem cells (hESCs), but is expressed in differentiated or post-mitotic cardiomyocytes and continues to be expressed in fetal, neonatal, and adult cardiomyocytes [7– 9]. [score:5]
The inhibitory effect of miR-499 on Sox6 translation might also be observed in cardiac differentiation of P19CL6 cells. [score:5]
In contrast, the data from our study showed that miR-499 overexpression has no remarkable effect on the expression of GATA4 and Nkx-2.5; moreover, the cell proliferation was significantly enhanced in P-499 cells. [score:5]
P19CL6 cells at 0 d. Given that miR-499 might participate in the cardiac differentiation of P19CL6 cells, we established a cell line that stably overexpressed miR-499 (P19CL6-miR-499, hereafter referred to as P-499) in order to observe the impact of persistent miR-499 expression on cardiac differentiation. [score:5]
In P19CL6 and P-c3.1 cells, the percentage of cells in the G1 phase increased from 72.27% and 74.30% respectively at day 8, to 76.76% and 77.31% respectively at day 10, indicating that the cells had almost stopped proliferating and might have started undergoing terminal differentiation; on the other hand, in P-499 cells, the percentage of cells in the G1 phase on day 8 (63.09%) and day 10 (61.5%) were at the same level as on day 6, which suggests that overexpression of miR-499 may maintain cell proliferation and thus inhibit terminal differentiation (Figure 2B, S2A). [score:5]
As a potential target of miR-499, the expression of Sox6 is also late stage-specific. [score:5]
As three highly conserved predicted miR-499 -binding sites are reportedly present in Sox6-3’UTR and because of the known association between Sox6 and heart development, Sox6 is the most likely target gene of miR-499. [score:4]
Next, we performed an annexin V-FITC binding assay (Figure 6C, S4C) in the P-499 cell line to determine whether miR-499 inhibited apoptosis through its target Sox6. [score:4]
MiR-499 knock-down enhanced apoptosis in the late differentiation stage in P19CL6 cells, but overexpression of miR-499 resulted in a decrease in the apoptosis rate. [score:4]
In our experiments, not only did the endogenous Sox6 protein level decrease as a result of pre-miR-499 transfection, but also anti-499 transfection could upregulate the Sox6 protein level in P19CL6 cell-derived cardiomyocytes during the late stage of differentiation. [score:4]
Meanwhile, miR-499 knock-down in P19CL6 cells had similar effects to Sox6 overexpression. [score:4]
Furthermore, when we knockdown the endogenous miR-499, the expression of Sox6 was increased. [score:4]
Next, we tested whether knock-down of endogenous miR-499 could influence endogenous Sox6 expression. [score:4]
In conclusion, our results provide evidence for Sox6 being a target of miR-499, and for the role of both Sox6 and miR-499 in neonatal heart development. [score:4]
The early stage witnessed steady proliferation even as the cells began to differentiate; the expression of miR-499 and Sox6 was very low or undetectable at this stage. [score:3]
It is believed that one of the targets of miR-499 is Sox6, which is a member of the Sox transcription factor family and has been detected in a number of tissues [10, 11]. [score:3]
Numerous studies have demonstrated that miR-499 could target Sox6 via Sox6-3’UTR luciferase reporters [7, 8, 16, 17]. [score:3]
In P-499 cells, as Sox6 levels were markedly decreased by overexpression of miR-499, cyclin D1 was consequently maintained at a higher level than in P19CL6 cells, leading to continuous proliferation of differentiating cardiomyocytes during the late stage of differentiation. [score:3]
Using a well-established in vitro cardiomyocyte differentiation system, mouse P19CL6 cells, we found that miR-499 was highly expressed in the late stage of cardiac differentiation. [score:3]
Identification of P19CL6-miR-499 and P19CL6-Sox6 stable cell lines was performed by examination for expression of miR-499 and Sox6, respectively. [score:3]
It has been reported that transgenic mice expressing a high level of miR-499 had larger hearts and displayed contractile dysfunction. [score:3]
To examine the temporal expression profile of miR-499 during cardiomyocyte differentiation, qRT-PCR for miR-499 was performed. [score:3]
We first determined whether miR-499 promoted proliferation through its target Sox6. [score:3]
Therefore, miR-499 overexpression promotes cell proliferation. [score:3]
It should be noted that the endogenous miR-499 and Sox6 showed the opposite expression trend during the cardiac differentiation of P19CL6 cells. [score:3]
These results indicate that miR-499 may target cyclin D1 via Sox6. [score:3]
The overexpression of Sox6 could reverse the proliferation and anti-apoptosis effects of miR-499. [score:3]
MiR-499 might regulate cyclin D1 expression via its influence on Sox6. [score:3]
There are also some indications that miR-499 may target cyclin D1 via Sox6. [score:3]
Transgenic expression of miR-499 also effectively reduced the elevated Sox6 mRNA level in miR-208a [-/-] hearts and reduced the Sox6 mRNA level in skeletal muscles of MCK-miR-499 transgenic mice [19]. [score:3]
After 48 h of anti-499 transfection, Sox6 protein level was upregulated compared to the control groups (Figure 4D ), suggesting that the presumed repression of Sox6 by endogenous miR-499 could be attenuated by exogenous anti-499. [score:3]
We found that Sox6 and miR-499 are highly expressed during cardiomyocyte terminal differentiation. [score:3]
This supports already available evidence that Sox6 is a target of miR-499. [score:3]
Mouse Sox6-3’UTR has seven miR-499 target sites, three of which are conserved in its human, mouse, rat, dog and chicken counterparts. [score:3]
This is supported by our finding that overexpression of Sox6 reversed the enhanced proliferation and anti-apoptotic effects of miR-499. [score:3]
The expression of miR-499 was almost undetectable at day 0 and day 6, but increased gradually from day 8, indicating that miR-499 might have some biological function in the late stage of cardiac differentiation of P19CL6 cells (Figure 1C ). [score:3]
The results are given as relative value to the miR-499 expression level in P19CL6 cells at day 0 (0 d). [score:3]
Employing the same strategy described previously, after another 2 days of culture, we found that when Sox6 was overexpressed, the lower apoptosis rate induced by miR-499 was reversed to normal. [score:3]
In agreement with this, several studies have also reported that miR-499 is highly expressed in differentiated or post-mitotic cardiomyocytes but is almost absent or barely detectable in undifferentiated hCSCs [7], human cardiomyocyte progenitor cells (hCMPCs) [16] and hESCs [9]. [score:3]
As the maximum level of miR-499 expression was observed on day 12 of differentiation (Figure 1C ), P19CL6 cells were replated at day 12 of differentiation for anti-499 transfection. [score:3]
It was also found that miR-499 might exert its function by regulating cyclin D1 via its influence on Sox6. [score:2]
This indicates that the regulation of Sox6 by miR-499 is not only associated with cardiomyocyte differentiation but is also late stage-specific. [score:2]
miR-499 probably regulates the proliferation and apoptosis of P19CL6 cells in the late stage of cardiac differentiation via its effects on Sox6 and cyclin D1. [score:2]
MiR-499 was highly expressed in the late stage of cardiac differentiation in P19CL6 cells. [score:2]
Therefore, miR-499 knock-down increased the apoptosis rate of cells at the late differentiation stage. [score:2]
MiR-499 targeted Sox6 at the late stage of cardiac differentiation. [score:2]
MiR-499 is a cardiac-abundant miRNA. [score:1]
Pre-miR-499 duplex or scrambled negative control at a final concentration of 50 nM with Lipofectamine 2000 was added into each well. [score:1]
Therefore, we replated P19CL6 cells at day 8 of differentiation, for pre-miR-499 transfection. [score:1]
The flow cytometry analysis indicated that miR-499 had significant effects on cell proliferation in the late stage of differentiation but not in the early stage. [score:1]
The ventricular cardiomyocytes were transfected with pre-miR-499 or scrambled oligonucleotides. [score:1]
Sox6 reversed the proliferation and anti-apoptosis effects of miR-499. [score:1]
MiR-499 knock-down enhanced apoptosis of cells in the late differentiation stage. [score:1]
P-499, P19CL6 cells stably transfected with pcDNA3.1-miR-499 recombinant plasmid; Empty, P-499 cells transfected with pcDNA3.1 plasmid; Sox6, P-499 cells transfected with pcDNA3.1-Sox6 recombinant plasmid. [score:1]
Synthesis of pre-miR-499, anti-miR-499 and Sox6 siRNA oligonucleotides. [score:1]
In cells stably transfected with miR-499 (P-499 cells), it was found that miR-499 could promote the differentiation into cardiomyocytes at the early stage of cardiac differentiation. [score:1]
Moreover, under cardiac pressure overload by thoracic aortic banding, the hearts of miR-499 transgenic mice demonstrated accentuated cardiac enlargement and severe contractile dysfunction, but the cardiomyocyte size was almost normal [19]. [score:1]
The main aim of our study was to determine the association between Sox6 and miR-499 and its role during the process of cardiomyocyte differentiation and maturation. [score:1]
However, miR-499 and Sox6 were both highly expressed in the late stage, which is characterized by gradual decrease in proliferation. [score:1]
However, how miR-499 is turned on in the cardiac differentiation system is still unclear. [score:1]
Thus, a balance between cell proliferation and apoptosis is required, and miR-499 probably plays a role in this. [score:1]
When the cells reached approximately 50% confluence, P19CL6 cells were transfected with 2 µg pcDNA3.1-Sox6 plasmid, pcDNA3.1-miR-499 plasmid, or the control pcDNA3.1 plasmid using Lipofectamine 2000. [score:1]
However, the biological functions of miR-499 in differentiated cardiomyocytes or in cardiomyocyte differentiation is not very clear. [score:1]
To construct the miR-499 expression plasmid, a 453-bp DNA fragment encompassing pri-miR-499 was amplified by PCR from mouse genomic DNA, using the forward primer (XhoI site underlined) 5′-acac CTCGAGAGGTGAGGTCCAGACTGGGG-3′ and reverse primer (HindIII site underlined) 5′-gtac AAGCTTTGGTTAGGGAC CAGAGGGGA-3′. [score:1]
Anti-miR-499 is a 2′- O-methyl -modified single-stranded RNA: 5′-AAACAUCACUGCAAGUCUUAA-3′. [score:1]
We have noticed some controversial reports on the function of miR-499. [score:1]
Pre-miR-499, anti-miR-499, Sox6 siRNA and scrambled negative control were chemically synthesized by Genechem Co. [score:1]
Pre-miR-499 is single-stranded nucleotides containing two sequences that one is identical to mature miR-499, 5′-UUAAGACUUGCAGUGAUGUUU-3′, and another mimics the endogenous stem-loop. [score:1]
However, the biological functions of miR-499 in differentiated cardiomyocytes or in the cardiomyocyte differentiation process is not very clear. [score:1]
The Sox6-3’-UTR luciferase reporter was prepared by amplifying the 720-bp DNA fragment of Sox6-3’UTR, which harbors three highly conserved predicted miR-499 -binding sites. [score:1]
In addition, Sox6 mRNA levels were significantly reduced in neonatal rat cardiomyocytes after miR-499 transfection [17]. [score:1]
P-c3.1, P19CL6 cells stably transfected with pcDNA3.1 plasmid; P-499, P19CL6 cells stably transfected with pcDNA3.1-miR-499 recombinant plasmid; P-Sox6, P19CL6 cells stably transfected with pcDNA3.1-Sox6 recombinant plasmid. [score:1]
The plasmid was designated pcDNA3.1-miR-499. [score:1]
To further confirm that miR-499 could promote cardiomyocyte proliferation during terminal differentiation, we tested whether miR-499 could promote proliferation of neonatal rat cardiomyocytes. [score:1]
P-c3.1, P19CL6 cells stably transfected with pcDNA3.1 plasmid; P-499, P19CL6 cells stably transfected with pcDNA3.1-miR-499 recombinant plasmid. [score:1]
These results promoted us to investigate whether Sox6 is the target of miR-499 during cardiac differentiation of P19CL6 cells. [score:1]
0074504.g004 Figure 4. (A) A schematic diagram showing the three highly conserved predicted miR-499 -binding sites of Sox6-3’UTR. [score:1]
Using the annexin V-FITC binding assay, we found that miR-499 overexpression resulted in a decreased apoptosis rate in P-499 cells compared with P19CL6 and P-c3.1 cells from day 6 to day 12 (Figure 3A, S2C). [score:1]
P-499, P19CL6 cells stably transfected with pcDNA3.1-miR-499 recombinant plasmid; Empty, P-499 or mir-499 cells transfected with pcDNA3.1 plasmid; Sox6, P-499 or mir-499 cells transfected with pcDNA3.1-Sox6 recombinant plasmid. [score:1]
How the association between miR-499 and Sox6 is related with the differentiation process of cardiomyocytes needs to be elucidated. [score:1]
After 48 h of pre-miR-499 transfection, showed that the Sox6 protein level was reduced dramatically (Figure 4C ). [score:1]
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2
[+] score: 226
From a survey of microRNA target prediction programs including MiRanda, TargetScan, and Mirtarget, Sox6 emerged as an attractive candidate, given three potential miR-499 binding sites and potential roles for Sox6 in muscle and heart [36]– [38], [45], [46]. [score:7]
To determine the consequence of persistent miR-499 expression in pressure-overload stress, we first generated transgenic mice with increased levels of miR-499 in the heart by expressing miR-499 under control of the cardiac, alpha-myosin heavy chain (Myh6) promoter, as it confers increasing postnatal ventricular cardiomyocyte expression [42]– [44]. [score:7]
We hypothesized that miR-499 expression may be playing an important role in cardiac gene regulation given its expression pattern, its evolutionary conservation, and its decrement in pressure-overload conditions such as human aortic stenosis [40]. [score:6]
Elevated miR-499 levels are associated with cardiac hypertrophy in vivo We hypothesized that miR-499 expression may be playing an important role in cardiac gene regulation given its expression pattern, its evolutionary conservation, and its decrement in pressure-overload conditions such as human aortic stenosis [40]. [score:6]
We suspect the failure of normal miR-499 down-regulation in our transgenic mice disrupted the normal response to cardiac pressure stress; similar theories have recently been put forward for cardiac transgenic mice expressing miR-133a [53]. [score:6]
Similar to TG-17 mice expressing miR-499, mice deficient in Egr1 are normal at baseline, but have an impaired response to cardiac stress [49], as do transgenic mice expressing the Egr1-repressor, Nab1 [50]. [score:5]
Although the Sox6 3′UTR could be targeted by miR-499, as we and others have demonstrated [36]– [38], [46], Sox6 levels were not altered in the transgenic mice, suggesting that Sox6 was not targeted by increased miR-499 levels in vivo, or that additional compensatory mechanisms may be involved in vivo. [score:5]
To determine the dose-responsiveness of miR-499 sensitive genes, we analyzed gene expression in the higher miR-499 expressing TG-9 line at 17 days of age. [score:5]
Given the baseline hypertrophy in miR-499-transgenic mice, we hypothesized that miR-499 expression may alter genes important in this cellular program, either directly or indirectly. [score:5]
Initially, we examined genes predicted to be targets of miR-499 using a targeted approach. [score:5]
We assessed miR-499 expression in human tissue to confirm its potential relevance to human cardiac gene regulation. [score:4]
To test whether miR-499 directly or indirectly regulates the immediate early genes, we cloned the 3′ UTRs of the immediate early response genes and placed each downstream of luciferase and tested these in H9c2 and 293T cells. [score:4]
We amplified fragments containing miR-499 from genomic DNA using high-fi delity PCR (PlatinumTaq, Invitrogen) and directional cloning into pcDNA3.1-TOPO (Invitrogen) for expression studies in cell culture. [score:4]
Second, inhibition of miR-499 in culture led to increases in induced Egr1 and Fos levels, which demonstrates that this regulation is present even outside of the context of the cardiac transgene. [score:4]
Interestingly, in a study that analyzed microRNAs in human aortic valve stenosis, miR-499 levels were decreased [40], and it is possible that this decrement may regulate cardiac gene expression changes that are important in the physiologic response to cardiac pressure load. [score:4]
The limited magnitude of transcript changes by miR-499 suggests that the hypertrophic phenotype observed was not due to gross gene expression disruption. [score:3]
We verified that the predicted human miR-499 genomic region encoded the microRNA by cloning the pre-miR-499 region, expressing it in cell culture, and performing Northern blot analysis (Fig. 1C ). [score:3]
Elevated miR-499 levels affect cardiac gene expression and predispose to cardiac stress -induced dysfunction. [score:3]
First, Egr1 and Fos were the most diminished transcripts in TG-17 miR-499-altered hearts, suggesting a robust alteration in the immediate early gene expression program, while in TG-9 Egr1 was also altered (although Fos was not significantly changed). [score:3]
A second line of miR-499 transgenic mice, expressing relatively lower levels of miR-499 (line #17, TG-17), had hearts that appeared unremarkable under basal conditions (Fig. 3A ). [score:3]
miR-499 targeting of Sox6. [score:3]
We used an antisense morpholino to inhibit miR-499 generation in the ventricular cardiomyocyte line, H9c2. [score:3]
miR-499 is expressed in human heart and skeletal muscle. [score:3]
Consistent with a role for miR-499 in blunting the response to cardiac stress, asymptomatic miR-499 -expressing mice had an impaired response to pressure overload and accentuated cardiac dysfunction. [score:3]
The dot indicated in red (arrow) represents miR-499 expression. [score:3]
Furthermore, microRNA levels vary in many cardiac disease states [30], [39]– [41], and in cardiac samples from individuals with aortic stenosis leading to pressure-overload and heart failure, miR-499 levels are altered [40]. [score:3]
miR-499 Expressing Mice Are Predisposed to Stress-Induced Cardiac Dysfunction. [score:3]
We transfected 293T cells (ATCC) with miR-499 -expression construct or vector alone for RNA for positive and negative controls. [score:3]
High levels of miR-499 led to spontaneous cardiac contractile dysfunction, while more modest levels of transgenic expression conferred susceptibility to pressure -induced dysfunction. [score:3]
Modest levels of miR-499 expression results in mild hypertrophy. [score:3]
expressing higher levels of miR-499 (line #9 or TG-9) developed enlarged hearts (n = 16) as demonstrated by gross pathology at 5 weeks of life (Fig. 2B ). [score:3]
This suggests gene expression changes due to miR-499 that favor hypertrophy. [score:3]
Mice expressing lower levels of miR-499 (line #17 or TG-17) appeared normal under basal conditions (n = 20). [score:3]
Global microRNA expression profiling studies have identified miR-499 in the heart [32]– [35], however its function is just beginning to be elucidated. [score:3]
We transfected increasing amounts of miR-499 into 293T cells in culture and found dose -dependent inhibition of the Sox6 UTR-luciferase construct, however another cardiac microRNA, miR-133, had no effect regardless of the dose (Fig. 4A ). [score:3]
Sox6, which was a target for miR-499 in luciferase assays, was not altered in transgenic mice (1.0 fold, not significant). [score:2]
miR-499 may titrate the cardiac response to stress in part by regulating the immediate early gene response. [score:2]
Importantly, pathway analysis revealed enrichment for the GO terms sarcomere (P = 0.0074), contractile fiber part (P = 0.0085), myofibril (P = 0.0095), and contractile fiber (P = 0.010), further highlighting the potential role of miR-499 in regulating sarcomeric function in the heart. [score:2]
To express miR-499 in vivo, we amplified DNA surrounding the mouse pre-miR-499 region and cloned the 574-bp fragment into the alpha-myosin heavy chain promoter vector using the following primers and SalI linkers: 5′-CGT GTC GAC CAA GTC TGG GGT GAA AGA GAA G-3′ (forward), 5′-TGT GTC GAC GGT CAT GAG CTT GTT GAG GTT C-3′ (reverse) and injected into one-cell FVB/NCrl embryos before implantation in pseudopregnant females. [score:2]
0019481.g002 Figure 2 (A) Cardiac miR-499 expression levels (mean ± standard deviation) in transgenic mouse lines compared to littermate controls. [score:2]
These data are consistent with a role for miR-499 in regulating the immediate early gene response. [score:2]
RNA was prepared from the ventricles of postnatal day 17 miR-499 transgenic mice or littermate controls, and gene expression was compared by microarray analysis (Fig. 5A ). [score:2]
Knockdown of miR-499 levels led to an increase in Egr1 and Fos levels 30 min following immediate early gene response activation by serum (Fig. 6A ), however the effect was temporally limited, as it resolved by 60 min. [score:2]
A distinctive pattern of cardiac gene regulation mediated by miR-499. [score:2]
To modulate microRNA levels, miR-499 mimic or control mimic (Dharmacon) or a morpholino directed against the miR-499 precursor or a scrambled control morpholino (GeneTools) was electroporated (Amaxa) into H9c2 and allowed to recover overnight. [score:2]
miR-499 plays a role in myosin gene regulation [36]– [38], however the functional effects of altered microRNA dosage may depend on the tissue's physiologic state. [score:2]
The higher expressing miR-499 transgenic mice (TG-9) had larger hearts (Fig. 2C ) and increased heart-to-body weight ratios compared to littermate controls (Fig. 2D ), while the brain-to-body weight ratios were similar. [score:2]
The conserved intronic location of miR-499 is indicated between exons 20 and 21 in humans and exons 19 and 20 in mouse; arrows indicate the direction of transcription. [score:2]
These data suggested that miR-499 levels negatively regulate the stress -induced activation of Egr1 and this may be important in the cardiac response to stress and in hypertrophy. [score:2]
Sequence of morpholino directed against the miR-499 precursor 5′-ATG CAG AGG AGC TAA ACA TCA CTG C-3′ or a scrambled control morpholino 5′-GAT TGC GAA GAG TCT CAC AAG ACC A-3′. [score:2]
We established two transgenic lines, which varied in degree of miR-499 expression compared to littermate controls (Fig. 2A ). [score:2]
We verified that Sox6 was an in vitro target of miR-499 by cloning the Sox6 3′-UTR and then tested for microRNA repression by luciferase assays. [score:2]
miR-499 is distinct from miR-1 and miR-133 in that it is encoded in only one genomic locus. [score:1]
The observation that miR-499 transgenic mice develop or are predisposed to cardiac dysfunction may reflect the fact that the immediate early response genes hold a key position in the hierarchy of the cardiac transcriptional response to stress. [score:1]
The Immediate Early Gene Response is Altered by miR-499 Levels. [score:1]
miR-499 did not repress luciferase constructs with the Egr1, Egr2, or Fos UTRs (Fig. 6E ), whereas miR-499 repressed constructs containing the Sox6 3′UTR. [score:1]
miR-499 elevation predisposes to stress -induced cardiac dysfunction in vivo. [score:1]
To avoid changes secondary to heart failure, we used the miR-499 transgenic line (TG-17) that did not display overt cardiac dysfunction. [score:1]
Activation of Fos was not different in the miR-499 transgenic mice, similar to what we observed in cultured cells. [score:1]
Altered cardiac transcripts from global analysis of miR-499 TG hearts. [score:1]
Sox6 3′UTR -mediated repression by miR-499 was evident, however Egr1, Egr2, and Fos 3′UTRs were not repressed by miR-499 (n = 3 per condition, *P<0.05). [score:1]
To determine the tissue-specificity of miR-499, we surveyed various human tissue types by Northern blot; miR-499 was detected only in the heart and in skeletal muscle (Fig. 1D ) in agreement with what has been reported in mice [36], [37]. [score:1]
Conversely, introduction of miR-499 mimic lowered Egr1 levels in cell culture after serum stimulation (Fig. 6B ). [score:1]
0019481.g004 Figure 4. (A) The 3′UTR of Sox6 was placed downstream of a luciferase reporter construct and tested for repression by miR-499 in 293T cells. [score:1]
We present several lines of evidence that demonstrate that miR-499 levels fundamentally alter the immediate early gene response, which is known to be important in the cardiac stress response. [score:1]
In this study we show that elevated levels of miR-499 in hearts of transgenic mice result in cardiomyocyte hypertrophy and stress -dependent cardiac dysfunction. [score:1]
We assessed whether serum response factor (SRF), which is upstream of the immediate early genes, was altered in the miR-499 transgenics. [score:1]
miR-499 is an evolutionarily conserved muscle-specific microRNA that is encoded within the intron of myosin heavy chain 7B (Myh7B) and is highly enriched in the cardiac ventricles. [score:1]
Our studies support an association between elevated cardiac miR-499 levels and cardiac dysfunction, particularly in the setting of pressure overload. [score:1]
Since the 3′ UTRs of Egr1, Egr2, and Fos were insufficient to mediate miR-499 repression, we suspect they are affected by miR-499 in a yet unknown manner that is not dependent on altered SRF levels. [score:1]
miR-499 was among the top cardiac-enriched microRNAs (Fig. 1A, Table S1), along with the well-studied microRNAs, miR-1 and miR-133. [score:1]
We reasoned that the immediate early response genes may be playing a role in the hypertrophic phenotype for several reasons: 1) the immediate early response genes are rapidly altered in response to cardiac stress [8], [47], [48]; 2) perturbation of the immediate early response alters cardiac hypertrophy [49], [50]; and 3) immediate early genes are typically SRF -dependent, and the cardiac abnormalities in the miR-499 transgenic partially resembled that of mice where SRF was temporally deleted [51]. [score:1]
In silico analysis revealed that miR-499 was located in an intron of the human myosin heavy chain gene, MYH7B (Fig. 1E ), analogous to the arrangement in Myh7B in mice. [score:1]
Overall, these results suggest elevated miR-499 levels predispose the heart to cardiac dysfunction. [score:1]
We therefore hypothesize that miR-499 alters the cardiac response to stress in part by modulating the immediate early gene response. [score:1]
We identified a discrete set of altered transcripts in unmanipulated, normally functioning, miR-499 transgenic hearts, including natriuretic peptide precursor type B (Nppb), ß-MyHC (Myh7) and alpha 1 skeletal muscle actin (Acta1). [score:1]
Given the effect of miR-499 levels on the immediate early gene response, which is known to be involved in cardiac stress and hypertrophy [12]– [14], we hypothesized that increased miR-499 levels may predispose to stress -induced cardiac dysfunction. [score:1]
We verified the effect of miR-499 on the immediate early response genes by miR-499 gain- and loss-of-function in vitro. [score:1]
Membranes were probed with [32]P -labelled locked nucleic acid probe (Exiqon) or DNA oligonucleotide probe complementary to mature miR-499 or to U6. [score:1]
Human miR-499 is a conserved muscle-specific microRNA. [score:1]
In screening for microRNAs enriched in the human heart, we identified an abundant microRNA, miR-499, which has been the subject of several recent studies. [score:1]
miR-499 blunts the induction of the immediate early response genes. [score:1]
Interestingly, mice lacking the cardiac-specific microRNA miR-208a have decreased amounts of miR-499 [25], [36]. [score:1]
Each dot represents a single transcript from three miR-499 transgenic mice and three littermate controls. [score:1]
We therefore tested whether the TG-17 miR-499-transgenic mice, which had normal function at baseline, were predisposed to increased cardiac dysfunction upon cardiac pressure overload. [score:1]
Total RNA was isolated from ventricular tissue from three miR-499-transgenic mice (line #17, TG-17) and three littermate controls at postnatal day 17. [score:1]
The connection between miR-499 and the immediate early gene response is important since activation of this pathway is thought to precede further transcriptional responses to stress. [score:1]
Evaluation of genes reported to be dysregulated in miR-208a mutant mice revealed elevated levels of Egr1, Egr2, and Fos in the heart, suggesting a potential relationship between miR-499 and miR-208 in regulation of the immediate early gene response to cardiac stress. [score:1]
Table S2 Common genes altered in miR-499 transgenic lines, TG-17 and TG-9. For each gene, the gene symbol, genomic location, log ratios and fold change of TG versus WT are shown. [score:1]
miR-499 levels and mRNAs were quantified using RNA from transgenic mouse hearts and littermate controls. [score:1]
Using a transgenic mouse mo del, we found that elevated miR-499 levels caused cellular hypertrophy and cardiac dysfunction in a dose -dependent manner. [score:1]
Sox6 3′UTR -mediated repression increased as amounts of miR-499 was increased; this was not observed with miR-133 or when the UTR orientation was reversed, n = 3–4 transfections per condition, *P<0.05. [score:1]
miR-499 levels were increased 12.6-fold, in agreement with our microRNA qPCR results. [score:1]
miR-499-transgenic mice (TG-17) displayed a blunted activation of Egr1 in response to systemic administration of EGF (Fig. 6C ). [score:1]
Interestingly, a recent study [39] reported that miR-499 levels increase in human cardiac failure, and the findings in our transgenic mouse mo del may support a detrimental role for elevated miR-499 levels. [score:1]
Furthermore, we found miR-499 alters the immediate early gene response to cardiac stress, which may partially contribute to the effects of elevated miR-499. [score:1]
In this study, we found that elevated levels of miR-499 in the heart can lead to cardiomyocyte hypertrophy and cardiomyopathy in a dose -dependent manner. [score:1]
0019481.g003 Figure 3 (A) Gross appearance of hearts from miR-499 transgenic mice (line #17, TG-17) and littermate controls (WT) was similar. [score:1]
Here we investigate miR-499, a microRNA embedded within a ventricular-specific myosin heavy chain gene, which is expressed in heart and skeletal muscle. [score:1]
RNA from miR-499 transfected 293T cells or control vector -transfected cells was used as positive or negative controls (ctrl). [score:1]
First, to examine the miR-499:immediate early gene relationship independent of the potential complexity of the in vivo transgenic system, we tested whether the immediate early gene response was altered using cultured cells where miR-499 levels were manipulated. [score:1]
We also tested whether repression was lost when we transfected the reversed 3′UTR sequence construct with our miR-499 vector (250 ng). [score:1]
By genomic sequence alignment, miR-499 is completely conserved throughout evolution with the exception of a single nucleotide change in chicken (Fig. 1B ). [score:1]
Echo Assessment of miR-499 Transgenic Mice. [score:1]
When we compared SRF protein levels in WT and TG mice, there was no difference (Fig. 6D ), suggesting that the immediate early genes are regulated by miR-499 independent of SRF levels. [score:1]
0019481.g006 Figure 6(A) Egr1 and Fos mRNA levels by qPCR relative to Gapdh in the ventricular cell line H9c2, upon introduction of a morpholino (MO) that blocks miR-499 generation or a control MO. [score:1]
Elevated miR-499 levels are associated with cardiac hypertrophy in vivo. [score:1]
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Over -expression of miRNA499 induces the expression of myosin heavy-chain (MHC) and cardiac-specific transcription factors in mouse and human ESC [33], while the inhibition of miRNA499 impairs the cardiac differentiation process [18]. [score:7]
Of extreme relevance, WB analysis showed that the combination of miRNA499 plus miRNA133 upregulated the protein expression of both Cx43 and cTnT (Fig. 6B). [score:6]
Expression of cardiac cytoskeletal protein (α-sarcomeric actinin) and of other important proteins involved in cardiac excitation/contraction (EC)-coupling (Cav1.2, SERCA2a, and RyR2) was analyzed by ICC on EB coexpressing miRNA499 and miRNA133, selected from the same batch of EB showing caffeine-responsiveness. [score:5]
ICC further confirmed that miRNA499 and miRNA133 coexpression was able to induce the expression of cardiac-specific proteins like cTnT, Cx43, Serca2a, and Cav1.2 (Fig. 6C) even in the absence of DMSO. [score:5]
The coexpression of miRNA499 and miRNA133 further increased the expression of the atrial marker Mlc. [score:5]
At the 14 days time point, WB showed that miRNA1 alone had no effect on both Cx43 and cTnT, miRNA133 increased only the expression of cTnT, while miRNA499 was able to markedly increase the expression of both Cx43 and cTnT (Fig. 3A). [score:5]
Gene and protein expression analysis showed that miRNA499 and miRNA133 are able to induce the differentiation of AMSC into cells expressing typical cardiac markers such as Nkx2.5, GATA4, cTnT, Cx43, Ryr2, and Cav1.2. [score:5]
The over -expression of miRNA499 resulted in the upregulation of both genes compared with DMSO (Supporting Information Fig. S3A, S3B). [score:5]
Recently, it has been suggested that certain miRNA are powerful regulators of cardiac differentiation processes [32], and it has been shown that miRNA1, miRNA133, and miRNA499 are highly expressed in muscle cells [32]. [score:4]
Most importantly, by simultaneously over -expressing miRNA499 and miRNA133 the number of P19 cells expressing cTnI was 30-fold greater compared with the standard differentiation protocol. [score:4]
2A (Supporting Information Fig. S3C) and the ventricular marker IRX4 (Supporting Information Fig. S3D) were upregulated in P19 cells treated with pre-miRNA499 plus 133. [score:4]
Real-time PCR analysis showed that also in P19 cells not exposed to DMSO, treatment with miRNA499 and miRNA133 upregulated GATA4 (+4.9-fold, p < . [score:4]
On the contrary, the coexpression of miRNA1 with miRNA499 did not increase the expression of the two cardiac-specific proteins compared with miRNA499 alone (Fig. 3A). [score:4]
The over -expression of miRNA1 alone or in association with miRNA499 failed to increase the expression level of the cardiac-specific differentiation markers considered. [score:4]
When miRNA499 and miRNA133 were coexpressed, we documented a significant increase in both GATA4 and Nkx2.5 expression compared with all other conditions tested (Fig. 2A, 2B). [score:4]
However, the coexpression of miRNA499 and miRNA133 resulted in a significantly higher expression of both cardiac markers compared with the other conditions tested (Fig. 7A). [score:4]
However, when we coexpressed miRNA499 together with miRNA133 the results were significantly and strikingly superior compared with the over -expression of miRNA499 alone. [score:4]
Also miRNA499 alone increased the expression of both Cx43 (+3.1-fold vs. [score:3]
In particular, coexpression of Cx43 and cTnT was always present in those cells forming beating clusters, confirming that both contractile and channels proteins are present in the EB treated with the combination of miRNA499 and 133. [score:3]
CMC derived from P19 cells over -expressing miRNA499 and miRNA133 develop EC-coupling properties typical of mature CMC. [score:3]
The Combination of miRNA499 and miRNA133 Increases the Expression of Cardiac-Specific Genes. [score:3]
Indeed, also miRNA499 alone induced a significant over -expression of GATA4 (+5.8-fold, p < . [score:3]
As already observed in P19 cells, the combination of miRNA499 with miRNA133 triggered the over -expression of both the nuclear transcription factor GATA4 (+13-fold, p < . [score:3]
The combination of miRNA499 and 133 greatly enhanced the expression of both Cx43 and cTnT (Fig. 3A). [score:3]
Coexpression of miRNA499 and miRNA133 induced a 3.5-fold increase in the number of responsive cells with respect to cells exposed to DMSO (p < . [score:3]
WB (Fig. 7B) and ICC (Fig. 7C,D) analysis confirmed that AMSC treated with miRNA499 and miRNA133 differentiated in cells expressing Cx43 and cTnT (Fig. 7B, 7C) but also Cav1.2 and Ryr2 (Fig. 7D). [score:3]
Coexpression of miRNA499 and miRNA133 sharply increased the proportion of caffeine-responsive cells. [score:3]
Treatment of P19 cells with miRNA499 or miRNA499 + 133 increased also the expression of the ventricular marker IRX4 (Supporting Information Fig. S3B). [score:3]
The expression of both GATA4 and Nkx2.5 was significantly increased by miRNA499 alone (Fig. 2A, 2B). [score:3]
WB and ICC analysis confirmed that cardiac proteins are indeed expressed at higher levels when P19 cells are cotransfected with miRNA499 plus miRNA133. [score:3]
In addition, the expression of genes encoding for cardiac-specific transcription factors, such as GATA4 and Nkx2.5, and cardiac-specific proteins, such as Cx43 and cTnT, was enhanced in cells treated with miRNA499 plus miRNA133. [score:3]
In particular, untreated EB showed responses compatible with Ca [2+] -dependent electrical activity, typical of immature CMC, while Na [+] -dependent excitability was recorded in EB over -expressing miRNA499 and miRNA133. [score:3]
Importantly for translational purposes, we have also shown that the same combination miRNA499 and miRNA133 is a powerful inducer of cardiac differentiation for human MSC. [score:3]
Cardiac-Specific Proteins Are Highly Expressed in P19 Cells Treated with miRNA499 and miRNA133. [score:3]
It is currently unknown whether the concomitant over -expression of miRNA1, miRNA133, and miRNA499 or if the combination of two of these miRNA would result in a synergistic action, further increasing the efficiency of cardiac differentiation. [score:3]
By simultaneously over -expressing miRNA499 and miRNA1, the number of beating EB significantly increased compared with: DMSO (+2.8-fold; p < . [score:2]
After 14 days, Cx43 was significantly over-expressed in cells treated with miRNA133 or miRNA499 and cTnT was significantly higher in the miRNA499 group compared with naïve cells (Fig. 7A). [score:2]
The Synergic Effect of miRNA499 and miRNA133 on AMSC. [score:1]
The synergistic effect exerted by the combination of miRNA133 and miRNA499 was confirmed by activation of the cTnI cardiac-specific promoter (Fig. 1B). [score:1]
Furthermore, the spontaneous mechanical activity response of miRNA499 and miRNA133 transfected cells to modulators of Ca [2+] handling effectors (CaV, RyRs, and IP3R) is consistent with that expected for cardiac but not skeletal muscle. [score:1]
miRNA499). [score:1]
DMSO, scramble miRNA, miRNA1, and miRNA499 + 1; #, p < . [score:1]
Finally, functional analysis showed that the percentage of responsive EB grown without DMSO but transfected with pre-miRNA499 and pre-miRNA133 did not significantly differ from the percentage of EB grown in the presence of 0.5% DMSO (Fig. 6D). [score:1]
It was impossible to document the same results using different combination of miRNAs, confirming that only the couple miRNA499/miRNA133 triggers the differentiation of MSC toward a cardiac-like phenotype. [score:1]
To verify whether miRNA499 and miRNA133 exert their effects also on other cell types, we tested our protocol on AMSC. [score:1]
Therefore, the effect of miRNA499 and miRNA133 synergism on cardiogenic differentiation was further tested based on the notion that mature excitation-contraction coupling relies on the presence of Ryrs-operated intracellular Ca [2+] stores. [score:1]
DMSO, scramble miRNA, miRNA1, and miRNA499 + 1). [score:1]
In particular, it has been clearly shown that miRNA133 and miRNA1 promote myoblast proliferation and differentiation, respectively, and that miRNA499 enhances the differentiation of cardiac progenitor cells into CMC [17– 20]. [score:1]
DMSO, scramble miRNA, miRNA1, miRNA133, and miRNA499 + 1, and p < . [score:1]
In summary, we demonstrated that miRNA499 and miRNA133 act in a synergic manner inducing P19 differentiation into CMC even in the absence of DMSO. [score:1]
DMSO, scramble miRNA, miRNA499 + 1; §, p < . [score:1]
miRNA499; ≠, p < . [score:1]
The treatment of EB with both pre-miRNA499 and pre-miRNA133 resulted in the strongest activation of the cTnI promoter (Fig. 1B). [score:1]
Figure 5MEA and twitch recordings of embryoid bodies treated with pre-miRNA499 together with pre-miRNA133. [score:1]
After 14 days, quantification of late cardiac-specific genes confirmed the synergistic effect exerted by miRNA499 and miRNA133 (Fig. 2C, 2D). [score:1]
Figure 7Amniotic mesenchymal stromal cells (AMSC) differentiation using miRNA499 and miRNA133 precursors. [score:1]
Further studies demonstrated that miRNA499 is highly enriched in cardiac committed adult progenitor cells [18] and human ESC [33]. [score:1]
Our results clearly showed that miRNA499 is a powerful activator of cardiac differentiation, particularly in comparison with miRNA1 and miRNA133. [score:1]
To strengthen our observation, we aimed to test whether treatment with miRNA499 plus miRNA133 in the absence of DMSO exposure was sufficient to trigger cardiac differentiation. [score:1]
miRNA precursors were diluted in Opti-MEM I medium at the following concentration: miRNA1 and miRNA499 precursors 10 nM, miRNA133 precursor and scrambled miRNA 5 nM. [score:1]
These data strongly suggest a synergistic effect of miRNA499 and miRNA133. [score:1]
001), and 2-fold versus miRNA499 alone (p < . [score:1]
Caffeine responsiveness was not significantly increased by any other treatment, thus supporting the specificity of miRNA499 + 133 effect (Fig. 4B). [score:1]
naïve, scramble miRNA, miRNA1, miRNA133, and miRNA499 + 1; †, p < . [score:1]
After 4 days, the EB were transferred to plastic culture dishes in the presence of differentiation medium, and transfected with precursor molecules (pre-miRNA) for miRNA499 (PM11352, 10 nM), miRNA1 (PM10617, 10 nM), and miRNA133 (PM10413, 5 nM) in different combinations or with scrambled miRNA used as a negative CTRL (AM17110, 5 nM) (Supporting Information Table S1). [score:1]
DMSO, scramble miRNA, miRNA1, miRNA133, and miRNA499 + 1; †, p < . [score:1]
In order to confirm the synergic action of miRNA499 with miRNA133, we tested this combination also in AMSC. [score:1]
miRNA499 + 1, p < . [score:1]
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[+] score: 136
Myostatin, a target gene of microRNA-208b and microRNA-499-5p and an inhibitor of muscle growth, is upregulated and inversely correlated with the expression of these microRNAs. [score:10]
Correlation between (C) MYH7 gene expression and microRNA-208b expression and (D) MYH7b gene expression and microRNA-499-5p expression in people with spinal cord injury and able-bodied control subjects. [score:9]
Correlation between (C) myostatin gene expression and microRNA-208b expression and (D) myostatin gene expression and microRNA-499-5p expression in people with spinal cord injury and able-bodied controls. [score:9]
Expression of microRNA-208b and microRNA-499-5p is decreased after spinal cord injury and correlates with expression of host genes MYH7 and MYH7bExpression of microRNA-208b and microRNA-499-5p progressively declined with time after spinal cord injury (Fig. 2). [score:7]
Direct modulation of gene target expression was studied in vivo by gene transfer of microRNA-208b or microRNA-499-5p in intact mouse muscle by electroporation. [score:6]
Our findings corroborate earlier studies describing a feedback loop regulating skeletal muscle mass (McCarthy et al. 2009; van Rooij et al. 2009), whereby decreased expression of MYH7 and MYH7b attenuate the expression of the encoded myomirs, microRNA-208b, and microRNA-499-5p. [score:6]
We also report that in vivo overexpression of microRNA-208b, but not microRNA-499-5p directly reduced myostatin gene expression in mouse skeletal muscle. [score:6]
Relative mRNA expression of myostatin decreased in skeletal muscle overexpressing microRNA-208b, but not microRNA-499-5p (Fig. 4C– D). [score:5]
Myostatin expression was inversely correlated with microRNA-208b and microRNA-499-5p expression in all groups (r =  0.702 and 0.637, respectively, P < 0.001, Fig. 3C– D). [score:5]
Furthermore, expression of both microRNA-208b and microRNA-499-5p correlated with expression of their respective host genes, namely MYH7 and MYH7b (r =  0.810 and 0.656, respectively, P <  0.001 Fig. 2C-D). [score:5]
Expression of microRNA-208b and microRNA-499-5p is decreased after spinal cord injury and correlates with expression of host genes MYH7 and MYH7b. [score:5]
Finally, overexpression of microRNA-208b, but not microRNA-499-5p, in adult rodent skeletal muscle decreased myostatin gene expression. [score:5]
Here, we demonstrate that overexpression of microRNA-208b, though not microRNA-499-5p, in rodent skeletal muscle decreased myostatin gene expression in vivo. [score:5]
Expression of microRNA-208b and microRNA-499-5p progressively declined with time after spinal cord injury (Fig. 2). [score:3]
MicroRNA-208b and microRNA-499-5p have nearly identical seed sequences and therefore share many predicted gene targets. [score:3]
Moreover, myostatin expression was inversely correlated with microRNA-208b and microRNA-499-5p in human skeletal muscle following spinal cord injury, coincident with skeletal muscle atrophy. [score:3]
Figure 2MicroRNA-208b (A) and microRNA-499-5p (B) expression in able-bodied control subjects (CON – white bar), and people with complete cervical spinal cord injury studied 1, 3, or 12 months post injury (gray bars) or after long-standing injury (LS – black bar). [score:3]
In conclusion, skeletal muscle expression of microRNA-208b and microRNA-499-5p progressively declined within the first year after cervical spinal cord injury in humans, with changes maintained in long-standing injury. [score:3]
MicroRNA-208b and microRNA-499-5p have similar seed regions that overlap by six bases, indicating that they share several target genes (van Rooij et al. 2009). [score:3]
The genes encoding slow-twitch oxidative type I muscle fiber myosin heavy chains, MYH7 and MYH7b, intronically express microRNA-208b and microRNA-499-5p, respectively (McCarthy et al. 2009). [score:3]
Here, we report that skeletal muscle expression of microRNA-208b and microRNA-499-5p, as well as their host genes MYH7 and MYH7b, decline progressively during the first year after cervical spinal cord injury in humans, with changes maintained in long-standing injury. [score:3]
Although myostatin has been validated as a target of both microRNA-208b (Callis et al. 2009) and microRNA-499-5p by luciferase assay (Bell et al. 2010), the in vivo regulation is unknown. [score:3]
Expression of microRNA-208b and microRNA-499-5p, as well as the slow myosin genes to which these particular microRNAs are intronic, decline progressively within the first year after spinal cord injury. [score:3]
Thus, we determined the expression of microRNA-208b, microRNA-499-5p, and myostatin in skeletal muscle obtained from people with complete spinal cord injury. [score:3]
The myostatin 3′ untranslated region (UTR) includes a mouse to human conserved seed -binding site for microRNA-208b and microRNA-499-5p (Fig. 3A). [score:3]
Hindlimb suspension for 28 days leads to skeletal muscle atrophy, concomitant with decreased expression of microRNA-208b and microRNA-499-5p in rat soleus muscle (McCarthy et al. 2009). [score:3]
In particular, microRNA-208b and microRNA-499-5p play a role in the regulation of skeletal muscle fiber type and skeletal muscle mass (McCarthy et al. 2009; van Rooij et al. 2009). [score:2]
With this method, we achieved an overexpression of microRNA-208b or microRNA-499-5p in predominantly glycolytic, type II, tibialis anterior muscle, respective to control muscle (Fig. 4A– B) that was comparable to levels measured in nontransfected oxidative soleus muscle (data not shown). [score:1]
Figure 3(A) Predicted microRNA seed/mRNA 3′-UTR interaction between microRNA-208b and microRNA-499-5p within the 3′-UTR of the human and mouse myostatin transcripts according to microRNA. [score:1]
Moreover, mice lacking both microRNA-208b and microRNA-499-p5 show a substantial loss of slow-twitch myofibers (van Rooij et al. 2009). [score:1]
MicroRNA-499-5p expression was approximately 33 and 90% lower at months 3 and 12 after injury, respectively, compared to the able-bodied control group (P < 0.05 and <0.001, Fig. 2B). [score:1]
Intact tibialis anterior mouse muscle was electroporated with either a control plasmid or plasmid encoding for pri-microRNA-208b or pri-microRNA-499-5p. [score:1]
Nevertheless, the role of microRNA-208b and microRNA-499-5p in the control of protein synthesis in human skeletal muscle has yet to be determined. [score:1]
The so-called myomir family is a group of microRNAs that includes microRNA-208a, microRNA-208b, and microRNA-499-5p, which fine-tune muscle morphology and function (McCarthy 2011). [score:1]
Tibialis anterior muscles of adult C57Bl/6J mice were electroporated with either a control plasmid or plasmid encoding for pri-microRNA-208b or pri-microRNA-499-5p (Origene, Rockville, MD) as described previously (Kulkarni et al., 2011). [score:1]
In individuals with long-standing injury, level of microRNA-499-5p was 2% of that observed in the able-bodied control group (P < 0.001). [score:1]
Whether microRNA-208b and microRNA-499-5p contribute to skeletal muscle atrophy in spinal cord injury is unknown. [score:1]
Given the known role of microRNA-208b and microRNA-499-5p in determining skeletal muscle size in rodents (van Rooij et al. 2009), we hypothesized that they may be altered, concomitant with skeletal muscle atrophy, in humans after spinal cord injury. [score:1]
In the mouse myostatin gene 3′-UTR there is an additional binding site for microRNA-499-5p (Fig. 3A). [score:1]
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[+] score: 120
Furthermore, overexpression of miR-499 or -1 results in upregulation of important cardiac myosin heavy-chain genes in embryoid bodies; miR-499 overexpression also causes upregulation of the cardiac transcription factor MEF2C. [score:11]
Compared to controls (WT, LV-BLANK), stable transduction of hESCs by LV-miR-499 or -1 did not affect the transcript expression of pluripotency genes (Oct4, Nanog) or upregulate cardiac genes (α myosin heavy chain or MHC, β myosin heavy chain, troponin T) that are not expressed in the undifferentiated state (p>0.05). [score:7]
We also showed that GATA4 is a probable target of miR-499 but not miR-1. However, our data did not allow us to exclude the possibility that GATA4 down-regulation was merely an indirect or secondary effect. [score:7]
Further analyses suggest that these events were orchestrated consequences of numerous cellular changes directly regulated by miR-499 and -1. Although miR-499 is up-regulated in human mesenchymal stem cells upon in vitro propagation [23], its role and involvement in human cardiogenesis or cardiac differentiation of hESCs has not been demonstrated. [score:6]
Among these, GATA4 is a predicted target of miR-499 but not miR-1. Consistent with this prediction, transduction of hE-CMs by LV-miR-499, but not LV-anti-miR-499, led to a 3-fold downregulation of GATA4 (p<0.05). [score:6]
An inhibitory effect of miR-499 on atrial specification would also lead to an increased percentage yield of ventricular derivatives and cannot be ruled out, although miR overexpression led to neither cytoxicity nor functional changes of atrial CMs. [score:5]
Interestingly, LV-miR-499, but not -anti-499 or –miR1, upregulated MEF2C (by ∼2.5-fold, p<0.05). [score:4]
In another separate study [49], we reported that miR-499 are strongly associated with cardiac differentiation and share many predicted targets with miR-208 that has been previously shown to associate with cardiac development. [score:4]
Consistent with our pre-differentiation transduction experiments already presented, LV-miR-499 transduction of hE-CMs likewise significantly upregulated α-MHC, β-MHC, as well as myosin light chain (MLC) 2v, α-actin and troponin T (p<0.05; Figure 2C). [score:4]
Our finding that pre- and post-differentiation transduction with LV-miR-499 similarly led to β-MHC upregulation hints at the possibility that miR-499 exerts its pro-cardiogenic action after cardiac differentiation is initiated. [score:4]
Similar to the pro-cardiogenic role of miR-1, β-MHC also became significantly upregulated (2.5-fold; p<0.05) in EBs from stably LV-miR-499-transduced hESCs, although α-MHC was unaffected (p>0.05). [score:4]
Indeed, MEF2C that is required for contractile protein activation also remains unchanged even after successful stable suppression of miR-499 by LV-anti-miR-499. [score:3]
Indeed, miR-499 and miR-1 shared a number of overlapping targets including those that are known to play important roles in early cardiogenesis. [score:3]
Most recently, Hosoda et al shows that miR-499 targets Sox6 and Rod1, traverses gap junction channels and translocates to structurally coupled human cardiac stem cells, enhancing their cardiomyogenesis in vitro and after infarction in vivo [48]. [score:3]
Similar to the reciprocal relationship described for normal and failing adult human CMs [14], we identified multiple functional groups of transcripts that were expressed at low levels (i. e. green) in the miR-1 and miR-499 abundant hE-, hF- and hA-VCMs. [score:3]
Indeed, the lack of effect of anti-miR-499 is consistent with its lack of expression in undifferentiated hESCs but a cardiac fate has been acquired. [score:3]
Our present study reports that miR-499 promotes ventricular specification and significantly augments β-MHC expression in hE-CMs, although it has no effect on the electrophysiological and Ca [2+]-handling properties. [score:3]
By contrast, the expression levels of α-MHC and β-MHC were not different between WT and LV-anti-miR-499 hESC-derived EBs. [score:3]
Using an elegant transgenic mouse mo del, they demonstrated that miR-208a is required for expression of β-MHC/miR-499 but its cardiac functions can be replaced by miR-499, suggesting the latter as a downstream mediator. [score:3]
Functionally, LV-miR-499 transduction of hESC-derived cardiovascular progenitors significantly increased the yield of hE-VCMs (to 72% from 48% of control; p<0.05) and contractile protein expression without affecting their electrophysiological properties (p>0.05). [score:3]
Identification of additional common and distinct targets of miR-499 and -1 requires extensive validation but could help dissect their overlapping and differential roles in cardiac differentiation. [score:3]
This notion is supported by the finding that miR-499 over -expression increases the ventricular yield, although miR-499 per se may not be absolutely necessary for initiating cardiac differentiation. [score:3]
These results suggested that overexpression of miR-499 or -1 alone was insufficient to drive cardiac differentiation or compromise pluripotency. [score:3]
During the course of our manuscript preparation, van Rooij et al reported that a family of miRs encoded by myosin genes, including miR-499, governs myosin expression and muscle performance [46]. [score:3]
According to these analyses, miR-499 is most closely associated with the regulation of embryonic stemness, cell proliferation, cell size and apoptosis; whereas, miR-1 is implicated in control of embryonic stemness, cell cycle, hypertrophy and cell size. [score:2]
As cardiac differentiation continues, ventricular specification occurs following cellular changes in cell proliferation, size and apoptosis that are mediated by miR-499. [score:1]
In the present study, we have identified miR-499 and -1 as determinants of ventricular specification and maturation of human CMs, respectively. [score:1]
We conclude that miR-1 and -499 play differential roles in human cardiac differentiation: While miR-499 promotes ventricular specification in the context of hESC-derived cardiovascular progenitors, miR-1 serves to facilitate their electrophysiological maturation. [score:1]
Our present study focuses on and further demonstrates the functional implications of miR-499 and -1 in the context of cellular electrophysiological and Ca [2+]-handling properties. [score:1]
Specifically, our experiments demonstrate that miR-499 promotes ventricular specification while miR-1 serves to facilitate their electrophysiological maturation. [score:1]
Taken collectively, these independent studies and ours strongly suggest an important biological role of miR-499 in cardiac differentiation. [score:1]
The profiles of miR-1, let-7a, let-7b, miR-26b, miR-30b, miR-125a, miR-126, miR-133a, miR-143, and miR-499 in hE/F/A-VCM were confirmed by qPCR (Figure 1B). [score:1]
A) Representative AP tracings of Control, LV-miR-1- and -miR-499-transduced hESC-derived ventricular derivatives as labeled. [score:1]
Indeed, although stably LV-anti-miR-499-transduced hESCs could differentiate into hE-CMs, our preliminary experiments of injecting zebrafish embryos with miR-499 or -1 anti-sense probes, but not blank or scrambled sequences, led to significant anatomical and functional heart defects, suggestive of an in vivo role. [score:1]
Interestingly, miR-499 is located within intron 20 of MYH7B on chromosome 20 and is highly conserved in vertebrates. [score:1]
This is consistent with the finding that stably LV-anti-miR-499-transduced hESCs were able to efficiently differentiate into hE-CMs with levels of GATA4, α-MHC and β-MHC not different from those of WT EBs. [score:1]
0027417.g003 Figure 3A) Representative AP tracings of Control, LV-miR-1- and -miR-499-transduced hESC-derived ventricular derivatives as labeled. [score:1]
B) The percentage distribution of ventricular, atrial and pacemaker phenotypes before and after LV-miR-1 or -miR-499 transduction. [score:1]
Figure S4 Representative AP tracings of Control, LV-miR-1- and -miR-499-transduced hE-ACMs, and bar graphs summarizing the AP parameters of the groups. [score:1]
In stark contrast, MESP1 was affected by none of LV-miR-1, miR-499 or –anti-miR-499 (p>0.05). [score:1]
We are proposing that upon the initiation of cardiac differentiation, miR-499 serves to promote ventricular specification. [score:1]
While miR-499 promotes ventricular specification of hESCs, miR-1 serves to facilitate electrophysiological maturation. [score:1]
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[+] score: 99
Other miRNAs from this paper: rno-mir-499
If the relaxin-3/RXFP3 system were to compensate for the reduced levels of relaxin-3 following infusion of rAAV1/2 EmGFP miR499, one mechanism could be the up-regulation of RXFP3 expression in nuclei that receive relaxin-3 projections. [score:6]
Despite substantial and significant reductions in hindbrain relaxin-3 expression, expression of RXFP3 was unchanged in the hindbrain of rAAV1/2 EmGFP miR499 treated animals (Figure 5C). [score:5]
Together, these results suggest neurons transduced by rAAV1/2 EmGFP miR499 are relatively healthy as they are still capable of expressing proteins other than relaxin-3. Therefore, the silencing of relaxin-3 is specific and unlikely to be due to effects on neuronal health or protein expression. [score:5]
In vitro, all three miRs significantly reduced relaxin-3 expression, with miR499 (Figure S1) exerting the greatest silencing effect resulting in a 5-fold reduction in expression. [score:5]
rAAV1/2 EmGFP miR499 infusion reduced hindbrain relaxin-3 expression to between 7.2 and 21.1% of the average level of the saline infused group, which corresponds to an average expression of 13.4% across the group. [score:5]
Three weeks after bilateral infusion of rAAV1/2 EmGFP miR499 into the NI, the EmGFP transgene was robustly expressed, indicating viral transduction and coexpression of miR499 (Figure 2D). [score:5]
For example, if the relaxin-3/RXFP3 system were to compensate for the reduced levels of relaxin-3 following infusion of rAAV1/2 EmGFP miR499 by up -regulating expression of RXFP3 in nuclei that receive relaxin-3 projections, function could be maintained. [score:4]
0042300.g002 Figure 2 EmGFP transgene expression (A, D, G) and relaxin-3-like immunoreactivity (B, E) in no infusion controls (A, B, C) and following bilateral infusion of rAAV1/2 EmGFP miR499 (D, E, F) or rAAV1/2 EmGFP miRC (G, H, I). [score:3]
Thus, our current understanding of the stimuli responsible for relaxin-3 expression leads to the hypothesis that although relaxin-3 mRNA and peptide is reduced following administration of rAAV1/2 EmGFP miR499, in the absence of stimuli for relaxin-3 release, the residual peptide might accumulate in the neuron and when release occurs, levels are not substantially impaired. [score:3]
EmGFP (green) is expressed in cells transduced by rAAV1/2 EmGFP miR499. [score:3]
0042300.g004 Figure 4 EmGFP (green) is expressed in cells transduced by rAAV1/2 EmGFP miR499. [score:3]
In rats that received an infusion of rAAV1/2 EmGFP miR499 6 weeks prior (n = 4), there was strong expression of NeuN, in the presence of EmGFP and the absence of relaxin-3-LI (Figure S2A). [score:3]
The average relaxin-3 expression in rats of the rAAV1/2 EmGFP miR499 treatment group was only 13% of the equivalent saline infusion control group, verifying the KD already observed using immunohistochemistry. [score:3]
In vivo Silencing of Relaxin-3 Expression with rAAV1/2 EmGFP miR499. [score:3]
In several rats, the complete absence of relaxin-3-LI in the NI following a successfully targeted infusion of rAAV1/2 EmGFP miR499 indicated that the levels of relaxin-3 in the NI were substantially reduced. [score:3]
Time Course of Relaxin-3 Silencing and Transgene Expression Following rAAV1/2 EmGFP miR499 Treatment. [score:3]
EmGFP transgene expression (A, D, G) and relaxin-3-like immunoreactivity (B, E) in no infusion controls (A, B, C) and following bilateral infusion of rAAV1/2 EmGFP miR499 (D, E, F) or rAAV1/2 EmGFP miRC (G, H, I). [score:3]
The structure of the engineered miR499 pre-miRNA sequence includes the antisense target sequence (light purple), the loop sequence (light blue) and the sense sequence with a two-nucleotide deletion (Δ2nt, orange). [score:3]
Whilst it was interesting to note, the neurons of the neighbouring dorsal tegmental nucleus remained untransduced, it was not important to restrict transduction to the NI, as the expression of miR499 would be expected to have no effect on neurons that did not produce relaxin-3. Immunohistochemical analysis of relaxin-3 following infusion of rAAV1/2 EmGFP miR499 established that the silencing observed in vitro [30] was recapitulated in vivo. [score:3]
In order to determine the optimal time to begin phenotypic analyses following vector infusion, we investigated the temporal profile of EmGFP transgene expression and relaxin-3 silencing following bilateral infusion of rAAV1/2 EmGFP miR499 (6×10 [7] gc, n = 4 rats per time point). [score:1]
However, in rats that received NI infusions of rAAV1/2 EmGFP miR499, the density of relaxin-3-LI fibres in the MS is markedly reduced. [score:1]
Success in using rAAV1/2 EmGFP miR499 treatment to produce adult rats with reduced relaxin-3 enabled examination of endogenous relaxin-3 function. [score:1]
Cells were transfected using the calcium phosphate method with 50 µg DNA consisting of equimolar amounts of pAM-EmGFP (vector, miRC or miR499) and the two helper plasmids, pDPI and pDPII [45]. [score:1]
In rAAV1/2 EmGFP miR499 transduced neurons of the NI, high power images demonstrate the Nissl substance was localised in the neuronal soma (Figure S2B). [score:1]
Holm-Sidak post-hoc analysis revealed that the rAAV1/2 EmGFP miR499 treated group had significantly less hindbrain relaxin-3 than all other groups (vs EmGFP, t = 11.266, p = 2.31×10 [−10]; vs EmGFP miRC, t = 10.899, p = 4.21×10 [−10]; vs Saline, t = 10.477, p = 8.52×10 [−10]). [score:1]
A and B received no infusion, n = 4. C and D are 3 weeks following bilateral infusion of rAAV1/2 EmGFP miR499, n = 4. Scale bars indicate 1.5 mm (A, C) and 150 µm (B, D). [score:1]
Both rAAV1/2 EmGFP and rAAV1/2 EmGFP miRC treatment groups demonstrated greater variability in relaxin-3 mRNA levels than either saline or rAAV1/2 EmGFP miR499 treated groups. [score:1]
Four treatment groups were used in behavioural and biochemical studies; saline (n = 13), rAAV1/2 EmGFP (n = 14), rAAV1/2 EmGFP miRC (n = 13) and rAAV1/2 EmGFP miR499 (n = 14). [score:1]
0042300.g003 Figure 3 A and B received no infusion, n = 4. C and D are 3 weeks following bilateral infusion of rAAV1/2 EmGFP miR499, n = 4. Scale bars indicate 1.5 mm (A, C) and 150 µm (B, D). [score:1]
These results indicate that miR499 induced silencing of relaxin-3, reduces relaxin-3 at both the site of synthesis and in nerve fibres and terminals near the site of relaxin-3 release. [score:1]
It was initially thought that analysing data from rats based simply on their treatments may have influenced the results, as not all rats in the rAAV1/2 EmGFP miR499 group would have identical KD. [score:1]
Given the role identified for the relaxin-3/RXFP3 system in the MS and the generation of hippocampal theta rhythm, it was important to assess the anxiety of rats following administration of rAAV1/2 EmGFP miR499. [score:1]
Holm-Sidak post-hoc analysis revealed that rAAV1/2 EmGFP miR499 had significantly higher blood glucose levels than rAAV1/2 EmGFP treated rats (difference of means = 0.530, t = 2.980, p = 0.007). [score:1]
Thus, miR499 was adopted for in vivo studies. [score:1]
On the basis of these findings, rAAV1/2 EmGFP miR499 infusion and the resultant reductions in relaxin-3 were hypothesised to impair spatial learning and memory. [score:1]
Saline n = 13, EmGFP n = 14, miRC n = 13, miR499 n = 14. [score:1]
rAAV1/2 EmGFP miR499 reduces relaxin-3-like immunoreactivity in nucleus incertus. [score:1]
The EmGFP miR499 cassette from pcDNA6.2 was cloned into the pAM plasmid, which was packaged into mosaic serotype 1/2 capsids. [score:1]
Hindbrain relaxin-3 mRNA is reduced following rAAV1/2 EmGFP miR499 treatment whereas RXFP3 mRNA remains unchanged. [score:1]
The same was true for both 6 and 9 weeks following rAAV1/2 EmGFP miR499 infusion (Figure 4C, D). [score:1]
To test the silencing efficacy of rAAV1/2 EmGFP miR499 in vivo, male Sprague Dawley rats received bilateral infusions of rAAV1/2 EmGFP miR499 (6×10 [7] gc, n = 4) into the NI, whereas control rats received either no infusion or rAAV1/2 EmGFP miRC (2.4×10 [8] gc, n = 4). [score:1]
rAAV1/2 EmGFP miR499 reduces relaxin-3-like immunoreactivity in fibres of the septum. [score:1]
Bilateral infusions of 2 µl rAAV (rAAV1/2 EmGFP 1.1×10 [8] gc/µl, rAAV1/2 EmGFP miRC 4.5×10 [7] gc/µl, rAAV1/2 EmGFP miR499 5×10 [7] gc/µl) or saline were made into the NI (AP −9.5 mm, ML±0.5 mm, DV −7.6 mm from bregma according the rat stereotaxic atlas [49]). [score:1]
Figure S1 Schematic representation of parent miR499 construct. [score:1]
Consequently, we tested whether administration of rAAV1/2 EmGFP miR499 and relaxin-3 silencing affected RXFP3 mRNA levels in hindbrain mRNA samples from the same subset of rats used for relaxin-3 mRNA quantitation. [score:1]
Figure S2 Histological assessment of neuronal health following rAAV1/2 EmGFP miR499 infusion. [score:1]
rAAV1/2 EmGFP miR499 reduces relaxin-3-like immunoreactivity from one week post infusion. [score:1]
[1 to 20 of 47 sentences]
7
[+] score: 88
Since miR-499 inhibits the Wnt and calcineurin signaling pathways through the suppression of target genes that construct these pathways, it has been expected that miR-499 might be a good candidate for cancer treatment (Scheme 1). [score:7]
For systemic administration and tumor targeting, we modified the Ala-Pro-Arg-Pro-Gly (APRPG) peptide on the surface of miR-499/TEPA-PCL (APRPG-miR-499) and showed that APRPG-miR-499 significantly suppresses tumor growth through silencing of target genes in Colon 26 NL-17-carcinoma–grafted mice [5]. [score:7]
These data indicate that a low dose of miR-499 mainly improved blood flow due to the normalization of incomplete tumor blood vessels, and a high dose mainly reduced blood vessels themselves due to the suppression of angiogenesis, resulting in the inhibition of tumor growth. [score:5]
We consider that miR-499 regulated the balance of pro-angiogenic factors and anti-angiogenic ones by inhibiting VEGF secretion. [score:4]
miR-499 is one of the miRNAs that regulate the expression of several genes, especially under hypoxia/ischemia conditions such as those found in cancer, myocardial infarction, and so on [1]. [score:4]
Previously we reported that miR-499 inhibits the capillary tube networks in vitro [5]. [score:3]
Our findings suggest that miR-499 could enhance the accumulation of DOX in the tumors due to the development of a favorable environment for drug delivery via VEGF regulation. [score:3]
Cholesterol-conjugated non -targeting miRNA (miCont-C) instead of miR-499-C was used to prepare APRPG -modified miCont-C/TEPA-PCL lipoplex (APRPG-miCont). [score:3]
Therefore, it would be expected that APRPG -modified TEPA-PCL would enable miR-499 to arrive at the tumor tissues and to become internalized effectively in the target cells. [score:3]
1. Wilson K. D. Hu S. Venkatasubrahmanyam S. Fu J. -D. Sun N. Abilez O. J. Baugh J. J. A. Jia F. Ghosh Z. Li R. A. Dynamic microRNA expression programs during cardiac differentiation of human embryonic stem cells: Role for miR-499 Circ. [score:3]
Although APRPG-miR-499 did not inhibit the tumor growth with a single injection at a dose of 2 mg/kg as miR-499 (Figure 3A), it did enhance the antitumor effect of DOX (Figure 3B). [score:3]
Previously, we reported that APRPG-miR-499 monotherapy caused a significant inhibition of tumor growth when given twice to mice bearing smaller tumors at a dose of 2 mg/kg/day as miR-499 [5]. [score:3]
Indeed, we showed earlier that miR-499 suppresses the growth of tumor cells and the capillary tube formation of human umbilical vein endothelial cells (HUVECs) in vitro [5]. [score:3]
Furthermore, the tumor growth was suppressed significantly with DOX and miR-499 combination therapy compared with DOX monotherapy. [score:2]
In order to apply them to systemic administration, miR-499-C/TEPA-PCL were modified with APRPG-PEG-DSPE. [score:1]
The sequences of the strands were as follows: miR-499-5p: 5′-UUAAGACUUGCAGUGAUGUUU-3′, miR-499-3p: 5′-AACAUCACAGCAAGUCUGUGCU-3′. [score:1]
APRPG-miR-499 or APRPG-miCont (2 mg/kg as miRNA) lipoplexes were intravenously injected into the tumor-bearing mice seven days after the implantation. [score:1]
Amelioration of Incomplete Blood Flow in Tumors Treated with miR-499. [score:1]
It is known that miR-499 is involved in particular signaling pathways including Wnt signaling and calcineurin pathways [1, 2]. [score:1]
On the other hand, for the combination therapy, the tumor-bearing mice were administered APRPG-miR-499 or APRPG-miCont (2 mg/kg as miRNAs) intravenously as described above. [score:1]
Cholesterol-conjugated miR-499 (miR-499-C) and cholesterol-conjugated control miRNA (miCont-C) were purchased from Hokkaido System Science (Hokkaido, Japan). [score:1]
For the therapeutic experiment, tumor-bearing mice were intravenously administered APRPG-miR-499 and/or DOX. [score:1]
Figure 2Improvement of DOX accumulation in tumors treated with miR-499. [score:1]
In addition, the accumulation of DOX in the tumor tissue was also increased after the treatment with APRPG-miR-499. [score:1]
The proportion of vessels with blood perfusion was about 60% in the APRPG-miCont–treated group; however, more than 90% of the vessels had blood flow after the APRPG-miR-499 treatment, indicating that miR-499 might have affected the improvement of tumor blood vessels. [score:1]
Quantitative analysis showed that the tumor vessels that had been treated with APRPG-miR-499 had blood flow about 1.5 times higher than that of the other groups, although the number of blood vessels was not significantly different between APRPG-miR-499 and APRPG-miCont (Figure 1B). [score:1]
Since the tumor blood vessels treated with miR-499 had the blood perfusion as mentioned, a high amount of DOX was carried to the tumor tissue with blood perfusion. [score:1]
Because the complexes of miR-499 and TEPA-PCL (lipoplexes) themselves had a strong positive charge (ca. [score:1]
Improvement of Doxorubicin (DOX) Accumulation in Tumors Treated with miR-499. [score:1]
We expect that combination therapy of miR-499 and DOX would enable patients to have reduced side effects and to maintain their quality of life at a high level. [score:1]
miR-499 was composed of miR-499-5p and miR-499-3p. [score:1]
APRPG-miR-499 or APRPG-miCont (2 mg/kg as miRNA) were administered intravenously seven days after the implantation. [score:1]
In the present study, we focused on the anti-angiogenic effect of miR-499. [score:1]
Taken together, our data indicate that miR-499 enhanced the effect of an anti-cancer drug, DOX, possibly through vascular normalization, suggesting that combination therapy with miR-499 and anti-cancer drugs can be a potential therapeutic strategy. [score:1]
APRPG-miR-499 or APRPG-miCont were administered intravenously seven days after implantation. [score:1]
We developed APRPG-miR-499 as a partner of DOX for combination therapy and examined its therapeutic effects in tumor-grafted mice. [score:1]
These data suggest that APRPG-miR-499 contributed to the normalization of blood flow in the tumor vessels, allowing DOX to accumulate in the tumor tissue and resulting in an enhanced antitumor effect of DOX. [score:1]
These results suggest that miR-499 could be a good candidate for increasing the efficacy of anti-cancer drugs. [score:1]
jcm-05-00010-f004_Scheme 1 Scheme 1 Associations of signaling pathways and miR-499. [score:1]
APRPG-miR-499 was administered intravenously when the tumor volume had reached 50 mm [3]. [score:1]
Previously, we developed a small RNA delivery system using tetraethylenepentamine -based polycation liposomes (TEPA-PCL) [6, 7, 8] and demonstrated that miR-499/TEPA-PCL reduces the secretion of VEGF and the production of other pro-angiogenic factors, e. g., CnAα and frizzled family receptor 8 (FZD8), in Colon 26 NL-17 mouse carcinoma cells [5]. [score:1]
Since it is shown that miR-499 could be a potential predictive biomarker in patients with lung cancer treated with chemotherapy [9], elucidation of miR-499 activity in vivo is of considerable interest. [score:1]
In the present study, we found that the tumor blood flow was increased significantly after the administration of APRPG-miR-499. [score:1]
The results showed that more DOX accumulated in the tumor tissue in the miR-499 -treated mice than in the other groups (Figure 2). [score:1]
APRPG-PEG-DSPE at a ratio of 10% of total lipids was incubated with miR-499-C/TEPA-PCL at 50 °C for 20 min to obtain APRPG -modified miR-499-C/TEPA-PCL lipoplex (APRPG-miR-499). [score:1]
Combination Therapy with miR-499 and DOX. [score:1]
Physicochemical properties of APRPG-miR-499 were as follows: particle size, 163 ± 13 nm; ζ-potential, −0.30 ± 0.46 mV. [score:1]
Figure 3Combination therapy with miR-499 and DOX. [score:1]
To form miR-499-C/TEPA-PCL lipoplexes, we mixed miR-499-C with TEPA-PCL in DEPC -treated water at a ratio of the nitrogen moiety derived from TEPA-PCL to the phosphorus from miR-499-C (N/P ratio) of 18 and incubated this mixture for 20 min at room temperature. [score:1]
[1 to 20 of 49 sentences]
8
[+] score: 42
We found that the NA segment significantly increased the expression of miR-155 and miR-674, whereas the HA segment significantly up-regulated the expression of miR-707, miR-674, and miR-499 (Figure 1A). [score:8]
Figure 4 A. The expressions of CD40, CD80/86, and MHCII on BMDCs when miR-155, miR-674, miR-499, and miR-181b1were inhibited (100 μg/ml inhibitor for each miRNA). [score:7]
A. The expressions of CD40, CD80/86, and MHCII on BMDCs when miR-155, miR-674, miR-499, and miR-181b1were inhibited (100 μg/ml inhibitor for each miRNA). [score:7]
Each 100 nM miRNAs inhibitors (miR155, miR499, miR674 and miR181b1) were transfected into BMDCs for 2h, before NA over -expression plasmid was transfected. [score:5]
Additionally, we identified four cellular miRNAs (miR-155, miR-674, miR-499, and miR-181b1) that were significantly up-regulated by NA. [score:4]
Figure 3 A. Flow cytometric analysis of the phenotypic alterations in DCs stimulated by miR155, miR499, miR375, miR674, or miR181b1 (i. e. the expressions of CD40, CD80/86, and MHCII on BMDCs stimulated by miRNAs). [score:3]
Moreover, NA did not increase the MFI of CD40- and MHCII -positive cells when miR-499 or miR-181b1was inhibited (P < 0.05) (Figure 4A and 4B). [score:3]
A. Flow cytometric analysis of the phenotypic alterations in DCs stimulated by miR155, miR499, miR375, miR674, or miR181b1 (i. e. the expressions of CD40, CD80/86, and MHCII on BMDCs stimulated by miRNAs). [score:3]
Primers were listed in Table 1. MiRNAs (miR-155, miR-674, miR-499 and miR-181b1) were amplified and cloned into pSilencer4.1 (Invitrogen), whose primers were listed in Table 2. The 3′-UTRs of Myo1d mRNAs target to miR-155 and the 3′-UTRs of Pgm2l1, Aldh18a1, Entpd6, Camk1d, Igf1r and Mbnl3 mRNAs, harboring the predicted miR-674 binding sequences, were amplified and cloned into pMIR-Report luciferase vector (Ambion, TX) with primers listed in Table 3. The shRNA target to Myo1d, Camk1d and Mbnl3 gene were designed and purchased from Invitrogen. [score:2]
[1 to 20 of 9 sentences]
9
[+] score: 39
Additional findings unique to Hltf null heart – decreased transcripts for Wt1 and Gata4 and their downstream targets, downregulation of transcripts for Brca1/BASC complex in DNA damage repair, disorganization of the collagen fibrillar network via decreased transcription of hypoxia-inducible factor (Hif-1a) and its downstream targets, and decreased transcripts for Myh7b/miR499 – demonstrate a critical role for Hltf in heart function. [score:8]
These findings emphasize the importance of regulation at the promoter where Gata4, Met2, E-box -binding factors, and five conserved elements (unknowns 1-5) control Myh7b/miR499 expression [37]. [score:4]
This is further evidence of Hltf’s secondary regulation of Gata4, this time via its direct transcriptional regulation of Myh7b/miR499. [score:4]
Hltf deletion also results in reduced expression of Myh7b/miR499. [score:3]
A common promoter (Figure 10) and co-transcriptional splicing of exon 7 regulate the myosin host gene Myh7b and its intronic miR499, which in turn regulates Gata4 [36]. [score:3]
The splicing machinery promotes miR499 expression in a tissue where Myh7b is not required. [score:3]
Concurrent transcriptional regulation of Myh7b/miR499 by Hltf. [score:2]
ChIP-PCR confirmed Hltf is recruited to the 228-bp regulatory region of the transcriptionally active Myh7b/miR499 promoter (Figure 2B, lane 2). [score:2]
The algorithm aided the identification of putative Hltf binding sites in the regulatory/promoter regions of the Gata4, Hif-1a and Myh7b/miR499 genes. [score:2]
Panel B, electrophoretic resolution of a single population of amplicons from touchdown PCR of ChIP confirmed Hltf bound the transcriptionally active regulatory regions of the promoters of Gata4 (248-bp; lane 1) and Myh7b/miR499 (228-bp; lane 2). [score:2]
One promoter [36] and co-transcriptional splicing [61, 62] regulate the protein-gene/MiRNA-gene unit, Myh7b/miR499. [score:2]
Future experimentation is required to validate individual Hltf sites in the Myh7b/miR499 gene promoter. [score:1]
Sequence of the Myh7b/miR499 promoter shows authentic transcription factor binding sites (B). [score:1]
A role for Hltf in the control of Myh7b/miR499 transcription indicates Hltf participates in the selection of myocardial muscle fiber type. [score:1]
Exclusion of Exon 7 introduces a premature termination codon subjecting Myh7b mRNA - that encodes the major slow-twitch type I myosin isoform - to nonsense mediated-decay, while retaining miR499. [score:1]
[1 to 20 of 15 sentences]
10
[+] score: 25
The miR-299a-3p, miR-302b-5p, miR-499 and miR-200c-3p were all up-regulated in EPO-MVs; the up-regulation of miR-499 and miR-200c-3p was significant (p < 0.001, n = 3). [score:7]
Our findings also demonstrate that miR-299, miR-499, miR-302, and miRNA-200 were upregulated in EPO-MVs (Fig.   8c). [score:4]
The miRNA profiles of the MVs revealed that EPO-MVs changed 212 miRNAs (fold-change ≥ 1.5), including miR-299, miR-499, miR-302, and miRNA-200, and that 70.28 % of these changes involved upregulation. [score:4]
d The bar plot shows the top ten enrichment score value of the significant enrichment pathway of the predicted possible target genes of miR-299a-3p, miR-302b-5p, miR-499 and miR-200c-3p. [score:3]
miR-499 plays an inhibitory role in the mitochondrial apoptosis pathway, and protects against H [2]O [2] -induced injury in cardiomyocytes [47]. [score:3]
e The plot shows top ten biologic functions from the predicted possible target genes of miR-299a-3p, miR-302b-5p, miR-499 and miR-200c-3p, P-value cutoff (p < 0.05). [score:3]
Jia Z, Zhang C, Sun M, Wang W, Chen P, Ma K, et al. miR-499 protects cardiomyocytes from H 2O 2 -induced apoptosis via its effects on Pdcd4 and Pacs2. [score:1]
[1 to 20 of 7 sentences]
11
[+] score: 23
Other miRNAs from this paper: hsa-let-7a-1, hsa-let-7a-2, hsa-let-7a-3, hsa-let-7b, hsa-let-7c, hsa-let-7d, hsa-let-7e, hsa-let-7f-1, hsa-let-7f-2, hsa-mir-15a, hsa-mir-16-1, hsa-mir-17, hsa-mir-18a, hsa-mir-19a, hsa-mir-19b-1, hsa-mir-20a, hsa-mir-22, hsa-mir-26a-1, hsa-mir-26b, hsa-mir-98, hsa-mir-101-1, hsa-mir-16-2, mmu-let-7g, mmu-let-7i, mmu-mir-1a-1, mmu-mir-15b, mmu-mir-101a, mmu-mir-126a, mmu-mir-130a, mmu-mir-133a-1, mmu-mir-142a, mmu-mir-181a-2, mmu-mir-194-1, hsa-mir-208a, hsa-mir-30c-2, mmu-mir-122, mmu-mir-143, hsa-mir-181a-2, hsa-mir-181b-1, hsa-mir-181c, hsa-mir-181a-1, mmu-let-7d, hsa-let-7g, hsa-let-7i, hsa-mir-1-2, hsa-mir-15b, hsa-mir-122, hsa-mir-130a, hsa-mir-133a-1, hsa-mir-133a-2, hsa-mir-142, hsa-mir-143, hsa-mir-126, hsa-mir-194-1, mmu-mir-30c-1, mmu-mir-30c-2, mmu-mir-208a, mmu-let-7a-1, mmu-let-7a-2, mmu-let-7b, mmu-let-7c-1, mmu-let-7c-2, mmu-let-7e, mmu-let-7f-1, mmu-let-7f-2, mmu-mir-15a, mmu-mir-16-1, mmu-mir-16-2, mmu-mir-18a, mmu-mir-20a, mmu-mir-22, mmu-mir-26a-1, mmu-mir-26b, mmu-mir-29c, mmu-mir-98, mmu-mir-326, rno-mir-326, rno-let-7d, rno-mir-20a, rno-mir-101b, mmu-mir-101b, hsa-mir-1-1, mmu-mir-1a-2, hsa-mir-181b-2, mmu-mir-17, mmu-mir-19a, mmu-mir-181a-1, mmu-mir-26a-2, mmu-mir-19b-1, mmu-mir-181b-1, mmu-mir-181c, hsa-mir-194-2, mmu-mir-194-2, hsa-mir-29c, hsa-mir-30c-1, hsa-mir-101-2, hsa-mir-26a-2, hsa-mir-378a, mmu-mir-378a, hsa-mir-326, mmu-mir-133a-2, mmu-mir-133b, hsa-mir-133b, mmu-mir-181b-2, rno-let-7a-1, rno-let-7a-2, rno-let-7b, rno-let-7c-1, rno-let-7c-2, rno-let-7e, rno-let-7f-1, rno-let-7f-2, rno-let-7i, rno-mir-15b, rno-mir-16, rno-mir-17-1, rno-mir-18a, rno-mir-19b-1, rno-mir-19a, rno-mir-22, rno-mir-26a, rno-mir-26b, rno-mir-29c-1, rno-mir-30c-1, rno-mir-30c-2, rno-mir-98, rno-mir-101a, rno-mir-122, rno-mir-126a, rno-mir-130a, rno-mir-133a, rno-mir-142, rno-mir-143, rno-mir-181c, rno-mir-181a-2, rno-mir-181b-1, rno-mir-181b-2, rno-mir-194-1, rno-mir-194-2, rno-mir-208a, rno-mir-181a-1, hsa-mir-423, hsa-mir-18b, hsa-mir-20b, hsa-mir-451a, mmu-mir-451a, rno-mir-451, ssc-mir-122, ssc-mir-15b, ssc-mir-181b-2, ssc-mir-19a, ssc-mir-20a, ssc-mir-26a, ssc-mir-326, ssc-mir-181c, ssc-let-7c, ssc-let-7f-1, ssc-let-7i, ssc-mir-18a, ssc-mir-29c, ssc-mir-30c-2, hsa-mir-484, hsa-mir-181d, hsa-mir-499a, rno-mir-1, rno-mir-133b, mmu-mir-484, mmu-mir-20b, rno-mir-20b, rno-mir-378a, rno-mir-499, hsa-mir-378d-2, mmu-mir-423, mmu-mir-181d, mmu-mir-18b, mmu-mir-208b, hsa-mir-208b, rno-mir-17-2, rno-mir-181d, rno-mir-423, rno-mir-484, mmu-mir-1b, ssc-mir-15a, ssc-mir-16-2, ssc-mir-16-1, ssc-mir-17, ssc-mir-130a, ssc-mir-101-1, ssc-mir-101-2, ssc-mir-133a-1, ssc-mir-1, ssc-mir-181a-1, ssc-let-7a-1, ssc-let-7e, ssc-let-7g, ssc-mir-378-1, ssc-mir-133b, ssc-mir-499, ssc-mir-143, ssc-mir-423, ssc-mir-181a-2, ssc-mir-181b-1, ssc-mir-181d, ssc-mir-98, ssc-mir-208b, ssc-mir-142, ssc-mir-19b-1, hsa-mir-378b, ssc-mir-22, rno-mir-126b, rno-mir-208b, rno-mir-133c, hsa-mir-378c, ssc-mir-194b, ssc-mir-133a-2, ssc-mir-484, ssc-mir-30c-1, ssc-mir-126, ssc-mir-378-2, ssc-mir-451, hsa-mir-378d-1, hsa-mir-378e, hsa-mir-378f, hsa-mir-378g, hsa-mir-378h, hsa-mir-378i, mmu-mir-378b, mmu-mir-101c, hsa-mir-451b, hsa-mir-499b, ssc-let-7a-2, ssc-mir-18b, hsa-mir-378j, rno-mir-378b, mmu-mir-133c, mmu-let-7j, mmu-mir-378c, mmu-mir-378d, mmu-mir-451b, ssc-let-7d, ssc-let-7f-2, ssc-mir-20b-1, ssc-mir-20b-2, ssc-mir-194a, mmu-let-7k, mmu-mir-126b, mmu-mir-142b, rno-let-7g, rno-mir-15a, ssc-mir-378b, rno-mir-29c-2, rno-mir-1b, ssc-mir-26b
Expression analysis of conserved miRNAs in 14 different tissue types revealed heart-specific expression of miR-499 and miR-208 and liver-specific expression of miR-122. [score:7]
A few notable exceptions are miR-499, an miRNA abundantly expressed in the heart (Figure 2A), which is represented by only one read (Table 2), and the miR-133 family, which is preferentially and abundantly expressed in the heart (Figure 2), and represented by only 7 reads (Table 1). [score:5]
Several miRNAs (miR-1, miR-133, miR-499, miR-208, miR-122, miR-194, miR-18, miR-142-3p, miR-101 and miR-143) have distinct tissue-specific expression patterns. [score:3]
miR-499 is abundantly and specifically expressed only in the heart and could not be detected in other tissues (Figure 2A). [score:3]
Because of their location within the introns of myosin genes and their specific expression in myogenic cells, miR-208 and miR-499 were referred to as MyomiRs [47]. [score:3]
Similar observations have been reported for miR-499 in zebra fish [50]. [score:1]
Similarly, miR-499 is another intronic-derived miRNA located in the Myh7b gene (MHC 7b). [score:1]
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12
[+] score: 20
Thus, miR-129 and miR-499 expression was downregulated upon induction of Aire among mature mTECs, yet both miRNAs were also downregulated in mature mTECs in Aire null mice as compared with WT. [score:8]
In the context of a putative role of miRNA in pGE, it is noteworthy that several mRNAs, upregulated upon mTEC maturation, showed tissue-specific expression patterns, i. e. being restricted to brain (miR-124 and miR-129), heart (miR-499), testis (miR-202), skin (miR-203) or embryo (miR-467 and miR-302). [score:6]
Mir-129, miR-499 and miR-302b were expressed at similar levels in immature mTECs of mutant and control littermates, but were significantly downregulated in mature mTECs of Aire null mutants (Fig. 2B). [score:6]
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13
[+] score: 19
Other miRNAs from this paper: mmu-mir-208a, dre-mir-499, mmu-mir-208b
A recent report on the regulation of Sox6 expression in zebrafish skeletal muscle has demonstrated that Sox6 transcription is positively regulated by MyoD and Myf5, and repression of Sox6 activity in slow fibers is maintained by miR-499 which targets the Sox6 3'-UTR [100]. [score:7]
Although the negative regulation of Sox6 by miR-499 has been already reported in mice [68, 97, 98], how suppression of Sox6 expression in slow fibers is initiated is not yet understood. [score:6]
It should be noted that miR-208, along with miR-499, also targets the 3'-UTR region of Sox6 [68, 97, 98]. [score:3]
Sox6 activity in slow fibers is suppressed by miR-499 which is encoded in an intron of the Myh7b gene. [score:3]
[1 to 20 of 4 sentences]
14
[+] score: 17
In addition to myofilament proteins, the expression of four microRNAs (miRNA, miR) involved in cardiac development and function was analysed (Fig. 2B): miR-133a and b, miR-1 and miR-499. [score:4]
3.4In addition to myofilament proteins, the expression of four microRNAs (miRNA, miR) involved in cardiac development and function was analysed (Fig. 2B): miR-133a and b, miR-1 and miR-499. [score:4]
MiR-499 plays a key role in inhibition of cardiomyocyte apoptosis through its suppression of calcineurin -mediated dephosphorylation of dynamin-related protein-1 [11] and has been implicated in myocardial regeneration [12]. [score:4]
MiR-499, which is highly expressed in the late stages of cardiac differentiation [9], was significantly up-regulated at day 4 and 14 post birth compared to adult mouse hearts. [score:4]
The zebrafish genome contains 3 loci encoding miR-499 in contrast to a single mammalian locus [10]. [score:1]
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15
[+] score: 17
IPost up-regulated miR-1, miR-15b, miR-21, miR-24, miR-26a, miR-27, miR-133a, miR-199a, miR-214, miR-208 and miR-499, while down-regulated miR-23a and miR-9 as compared with Sham group. [score:6]
Compared with sham group, the expressions of miR-1, miR-15b, miR-21, miR-24, miR-26a, miR-27, miR-133a, miR-199a, miR-214, miR-208 and miR-499 were increased in IPost hearts, while miR-9 and miR-23a were down-regulated in IPost mo dels. [score:5]
As previously reported, a collection of miRNAs were abnormally expressed in ischemic mouse hearts in response to I/R injury, such as miR-1, miR-9, miR-15b, miR-21, miR-23a, miR-24, miR-26a, miR-27, miR-133a, miR-199a, miR-208, miR-214 and miR-499 [20, 21, 28]. [score:3]
Then real-time quantitative PCR was performed to quantify the expression level of miR-1, miR-9, miR-15b, miR-21, miR-23a, miR-24, miR-26a, miR-27, miR-133a, miR-199a, miR-208, miR-214 and miR-499 with SYBR Green PCR Master Mix (Applied Biosystems) according to the manufacturer’s instructions. [score:3]
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16
[+] score: 17
Other miRNAs from this paper: mmu-mir-208a
over -expressing miR-499 down-regulated the immediate early response genes Egr1 and Fos, but up-regulated Nppb [23]. [score:9]
miR-499 lies within an intron of the Myh7b gene (also known as Myh14), which is up-regulated during surgically -induced cardiac hypertrophy in mice [24]. [score:4]
Although their induction is SRF -dependent, their expression can also be regulated in an SRF-independent manner via a microRNA, miR-499 [23]. [score:4]
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17
[+] score: 17
Other miRNAs from this paper: mmu-mir-208b
At P7, consistent with gene expression results of their host MyHC mRNAs (Fig.   2), the expression level of miR-208b was significantly reduced in Vgll2 [−/−] GPS muscles by 39%, whereas miR-499 expression was slightly increased (Fig.   6). [score:7]
Although these miRNAs share a comparable seed sequence and target the same mRNAs, they are differentially regulated: miR-208b is encoded within the Myh7 gene, and miR-499 is encoded within Myh7b gene [43]. [score:4]
Previous studies showed that two miRNAs, miR-208b and miR-499, serve as fiber-type modulators by inhibiting the activity of transcriptional repressors of genes encoding slow-twitch contractile proteins such as Sox6, Sp3, and Purβ 21, 39– 42. [score:3]
miR-208b and miR-499 expression levels in the GPS muscle from Vgll2 [+/+] and Vgll2 [−/−] mice at P7 (n = 8). [score:3]
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18
[+] score: 16
At 16 months, all 15 miRNAs were significantly downregulated in heart tissue of obese mice compared to heart tissue of normal mice: let-7f-5p (FC: 3.3), miR-10a-5p (FC: 2.6), miRNA-19b-3p (FC: 5.0), miR-25-3p (FC: 2.6), miR30e-5p (FC: 5.6), miR-140-5p (FC: 5.0), miR-155-5p (FC: 1.7), miR-146a-5p (FC: 4.0), miR-181b-5p (3.0), miR-199a-3p (FC: 3.6), miR-322 (FC: 1.5), miR-451 (FC: 1.9), miR-499-5p (FC: 5.4), miR-669m-5p (FC: 1.7) and miR-3473b (FC: 3.4). [score:3]
These data coincide with previous results where it showed that miR-499 levels were increased in failing and hypertrophied human hearts, and in animal mo dels of cardiac hypertrophy by miR-499 overexpression [47]. [score:3]
We found 8 circulating miRNAs that were less abundant in the obese mice than in normal mice, indicating an association between their gene expression in myocardium: let-7f-5p (FC: 5.4), miR-10a-5p (FC: 2.3), miRNA-19b-3p (FC: 2.5), miR-25-3p (FC: 3.4), miR-140-5p (FC: 4.5), miR-146a-5p (FC: 3.3), miR-181b-5p (FC: 5.2) and miR-499-5p (FC: 2.2). [score:3]
Regarding circulating miRNAs as potential biomarkers of diabetic cardiomyopathy, we found an association between differential miRNA expressions in myocardium and plasma at 16 months in 8 miRNAs (let-7f-5p, miR-10a-5p, miR-19b-3p, miR-25-3p, miR-140-5p, miR-146a-5p, miR-181b-5p, miR-499-5p). [score:3]
In our obese animal mo del, cardiac hypertrophy is present in spite of miR-499 being down regulated, showing that miR-208a/miR-499 pathway is not the driving force to generate the increase of heart mass and leaving open this possibility to other signal pathways like IGF-1, TGF-β or inflammatory cytokines related to diabetic cardiomyopathy (Table  1) 48, 49. [score:2]
Based on previous pre-clinic studies, the miRNAs validated by RT-qPCR in our study are involved in alteration of glucose and lipid metabolism via insulin pathways (let-7f-5p, miR-10a-5p, miR-322) 20– 22, in cardiomyocytes apoptosis (miR-19b-3p, miR-25-3p, miR-30e-5p, miR-140-5p, miR-199a-3p, miR-499) 23– 28, in mitochondrial function (miR-181a/b) [29], in pro-inflammatory signalling (miR-146a-5p, miR-155, miR-181b-3p, miR-3473b) 30– 33, and in cardiac hypertrophy (miR-451) [34] and myocardial fibrosis process (miR-19b) 35, 36. [score:1]
Recently, Zhang and colleagues reported that plasma miR-499 increase is detectable as early as 1 h after onset of chest pain in acute myocardial infarction, proposing it as a sensitive biomarker for early diagnosis of a cardiac ischemic event [46]. [score:1]
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[+] score: 14
The SVF from both miR-499 Tg and Sox6 m KO displayed inhibited differentiation compared to controls, based upon Oil Red O staining and qPCR analyses of adipogenic gene expression (Fig 3C–3F). [score:4]
The first mo del expresses miR-499 under the control of a muscle creatine kinase (MCK) promoter (miR-499 Tg) [23]. [score:3]
To attempt to identify factors from skeletal muscle that might underlie communication between skeletal muscle and adipose tissue, we interrogated microarray data from both miR-499 Tg and Sox6 m KO muscles [22]. [score:1]
The PPARγ-tTA, TRE-Cre, TRE-H2B-GFP, miR-499 Tg, MCK-Cre and Sox6 [fl/fl] mice were described previously and used to generate AdipoTrak or muscle-specific mouse lines [14, 22, 23]. [score:1]
R-spondin 3 Reduces Adipogenesis In VitroTo attempt to identify factors from skeletal muscle that might underlie communication between skeletal muscle and adipose tissue, we interrogated microarray data from both miR-499 Tg and Sox6 m KO muscles [22]. [score:1]
We found that miR-499 Tg and Sox6 m KO adipocyte nuclei had a significant decrease in BrdU incorporation (Fig 4G and 4H). [score:1]
Consistent with that notion, we found that miR-499 Tg mice exhibited less weight gain while receiving HFD (Fig 4A). [score:1]
To examine the effect of type I (slow) fibers on adiposity, we utilized two mouse strains (miR-499 Tg and Sox6 m KO) that have predominantly slow muscle fibers [22, 23]. [score:1]
To attempt to extend the cell culture findings to intact animals, we administered BrdU to miR-499 Tg and Sox6 m KO mice during the final week of the HFD regimen. [score:1]
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[+] score: 11
Interestingly, in embryonic stem cells, miR-499 upregulates the expression of heart-specific genes such as Nkx2.5 and MEF2C and regulates genes involved in the Wnt pathway 34. [score:7]
Another miRNA with an important function in heart development is miR-499, which represses the miR-499 target genes Sox6 and Rod1 in human CSCs, enhancing cardiomyogenesis in vitro and after infarction in vivo 24. [score:4]
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[+] score: 11
miR-208b and miR-499 were reported to control muscle fiber type by inhibiting fast muscle-specific genes while promoting slow myofiber genes. [score:3]
The results show that the levels of miR-23a, miR-206, and miR-499 were induced after 30 and 45 days of HDBR (Figures 4(b), 4(d), and 4(f)). [score:1]
As miR-499 repressed fast muscle-specific genes while activating slow myofiber genes, the secretion of miR-499 should facilitate the slow to fast myofiber type transition. [score:1]
Our results indicated that starvation induced C2C12 myotubes atrophy led to the secretion of miR-1, miR-23a, miR-133, miR-206, miR-208b, and miR-499 into the culture medium, which could be used as indicators for muscle atrophy. [score:1]
The correlation of the other three miRNAs was also provided in Supplementary Figure 2. These results indicated that serum levels of miR-23a, miR-206, and miR-499 might represent the extent of muscle degeneration following HDBR. [score:1]
In conclusion, analysis of miR-23a, miR-206, and miR-499 serum levels proved their potential to serve as powerful noninvasive prognostic biomarkers for muscle atrophy. [score:1]
Moreover, the levels of miR-23a, miR-206, and miR-499 increased during HU in a time -dependent manner. [score:1]
As expected, serum miR-23a, miR-206, and miR-499 levels were positively correlated with the ratio of soleus volume loss in subjects after 45 days of HDBR (Figure 5). [score:1]
There were significantly increased levels of miR-23a, miR-206, and miR-499 in serum of HDBR participants after 45 days of head-down bed rest. [score:1]
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22
[+] score: 11
For the first time we report that not only are the four cardiac-enriched miR-1, miR-133, miR-499 and miR-208 highly expressed in sheep LV, but also provide information on their isomiRs. [score:3]
Hsa-/mmu-/rno-miR-499a-5p and hsa-499b-3p were plentiful in sheep heart whereas the expression of other forms of miR-499 were low. [score:3]
Four myocardial-enriched miRNAs, miR-1, miR-133, miR-499 and miR-208, were confirmed to be highly expressed in ovine heart tissue. [score:3]
Cardiac-enriched miR-1-3p, miR-133a-3p, miR-133b-3p, miR-208b-3p and miR-499-3p were screened. [score:1]
MiR-1, miR-133, miR-499 and miR-208 are highly enriched myocardial miRNAs 27, 28 and are highly conserved across multiple species including human [29], mouse [30] rat [31] and porcine [32]. [score:1]
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[+] score: 10
5 microRNAs with a role in muscle biology: miR-26a (Dey et al. 2012), miR-499 (van Rooij et al. 2009a), miR34b (Roberts et al. 2012), miR-30c (Ketley et al. 2013) and miR-181a (Naguibneva et al. 2006) were validated as differentially expressed during ageing in the skeletal muscle of mice (Fig.   3a). [score:3]
Genes associated with ubiquitin -mediated proteolysis, cell cycle, NF-kB and insulin signalling, as well as miRs miR-132, miR-122, miR-499, miR-128 and miR-22 formed central nodes in the network of miRNA:target interactions disrupted during ageing (Fig. S2). [score:3]
The differential expression of miR-181a, miR-133a, miR-26a, miR-499, miR-34b and miR-30c was validated in muscle during ageing (Fig.   3a, b). [score:3]
Among the differentially expressed microRNAs were miR-181a, miR-208-5p or miR-499, miR-130a, miR-26a and miR-30c with previously characterised functions in skeletal muscle. [score:1]
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24
[+] score: 10
In addition, essential amino acids have been shown to promote muscle hypertrophy by not only suppressing Mstn levels but by inducing greater expression of miR-499, -208b, -23a, -1, and -206 [21]. [score:5]
Furthermore, over expression of miR-499 leads to reduced Mstn 3′UTR activity, suggesting that Mstn is a target of miR-499 [20]. [score:5]
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[+] score: 9
Three notable examples include: miR-499, a MyomiR that controls myosin heavy chain isoform expression [4] and is a biomarker of myocardial infarction [40]; miR-21, which is currently touted as a promising therapeutic target for cardiovascular diseases [41]; and miR-195, whose deletion in mice leads to cardiac hypertrophy [5]. [score:7]
Distribution of tag 3′ ends for miR-499 is from the heart biopsy, while HL-1 cell data is shown for miR-181a, miR-15a and miR-301a (miRBase-annotated 3′ end positions are boxed). [score:1]
There were three major types of 3′ end variability observed in our dataset (Figure 2G); a small range of 3′ end sites (most common, e. g. miR-499); a large spread of 3′ end sites used, perhaps indicating 3′ trimming (e. g. miR-181a); or a defined 3′ end site, albeit not necessarily as annotated in miRBase (e. g. miR-15a). [score:1]
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[+] score: 9
Highly expressed miRNAs in skeletal muscle tissue are termed myomiRs, which include miR-1, miR-133a, miR133-b, miR-206, miR-208, miR208b, miR486, and miR-499 (Van Rooij et al., 2008). [score:3]
In response to calcium signaling, miR-208b and miR-499 indeed reinforce slow fiber conversion by inducing the expression of β-MHC and Myh7b (Van Rooij et al., 2009). [score:3]
The fine-tuned expression of miR-499 and miR-208b plays a role in the control of skeletal muscle performance. [score:3]
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27
[+] score: 9
Other miRNAs from this paper: hsa-let-7a-1, hsa-let-7a-2, hsa-let-7a-3, hsa-mir-15a, hsa-mir-18a, hsa-mir-33a, hsa-mir-103a-2, hsa-mir-103a-1, hsa-mir-107, mmu-mir-27b, mmu-mir-126a, mmu-mir-128-1, mmu-mir-140, mmu-mir-146a, mmu-mir-152, mmu-mir-155, mmu-mir-191, hsa-mir-10a, hsa-mir-211, hsa-mir-218-1, hsa-mir-218-2, mmu-mir-297a-1, mmu-mir-297a-2, hsa-mir-27b, hsa-mir-128-1, hsa-mir-140, hsa-mir-152, hsa-mir-191, hsa-mir-126, hsa-mir-146a, mmu-let-7a-1, mmu-let-7a-2, mmu-mir-15a, mmu-mir-18a, mmu-mir-103-1, mmu-mir-103-2, mmu-mir-342, hsa-mir-155, mmu-mir-107, mmu-mir-10a, mmu-mir-218-1, mmu-mir-218-2, mmu-mir-33, mmu-mir-211, hsa-mir-374a, hsa-mir-342, gga-mir-33-1, gga-let-7a-3, gga-mir-155, gga-mir-18a, gga-mir-15a, gga-mir-218-1, gga-mir-103-2, gga-mir-107, gga-mir-128-1, gga-mir-140, gga-let-7a-1, gga-mir-146a, gga-mir-103-1, gga-mir-218-2, gga-mir-126, gga-let-7a-2, gga-mir-27b, mmu-mir-466a, mmu-mir-467a-1, hsa-mir-499a, hsa-mir-545, hsa-mir-593, hsa-mir-600, hsa-mir-33b, gga-mir-499, gga-mir-211, gga-mir-466, mmu-mir-675, mmu-mir-677, mmu-mir-467b, mmu-mir-297b, mmu-mir-717, hsa-mir-675, mmu-mir-297a-3, mmu-mir-297a-4, mmu-mir-297c, mmu-mir-466b-1, mmu-mir-466b-2, mmu-mir-466b-3, mmu-mir-466c-1, mmu-mir-466e, mmu-mir-466f-1, mmu-mir-466f-2, mmu-mir-466f-3, mmu-mir-466g, mmu-mir-466h, mmu-mir-467c, mmu-mir-467d, mmu-mir-466d, hsa-mir-297, mmu-mir-467e, mmu-mir-466l, mmu-mir-466i, mmu-mir-466f-4, mmu-mir-466k, mmu-mir-467f, mmu-mir-466j, mmu-mir-467g, mmu-mir-467h, hsa-mir-664a, hsa-mir-1306, hsa-mir-1307, gga-mir-1306, hsa-mir-103b-1, hsa-mir-103b-2, gga-mir-10a, mmu-mir-1306, mmu-mir-3064, mmu-mir-466m, mmu-mir-466o, mmu-mir-467a-2, mmu-mir-467a-3, mmu-mir-466c-2, mmu-mir-467a-4, mmu-mir-466b-4, mmu-mir-467a-5, mmu-mir-466b-5, mmu-mir-467a-6, mmu-mir-466b-6, mmu-mir-467a-7, mmu-mir-466b-7, mmu-mir-467a-8, mmu-mir-467a-9, mmu-mir-467a-10, mmu-mir-466p, mmu-mir-466n, mmu-mir-466b-8, hsa-mir-466, hsa-mir-3173, hsa-mir-3618, hsa-mir-3064, hsa-mir-499b, mmu-mir-466q, hsa-mir-664b, gga-mir-3064, mmu-mir-126b, gga-mir-33-2, mmu-mir-3618, mmu-mir-466c-3, gga-mir-191
Out of the 26 miRNA/host gene pairs with coordinated expression, 11 have been found to be coordinately expressed in both, human and mouse [19], [27], [59], [61]– [64], [67]– [69], [71], [73]– [79]: mir-103/ PANK3, mir-107/ PANK1, mir-126/ EGFL7, mir-128-1/ R3HDM1, mir-140/ WWP2, mir-211/ TRPM1, mir-218-1/ SLIT2, mir-218-2/ SLIT3, mir-27b/ C9orf3, mir-33/ SREBF2, and mir-499/ MYH7B. [score:5]
Moreover, two miRNA/host gene pairs have been found to have expression patterns associated with the same phenotype in both species: mir-499/ MYH7B with heart development [79] and mir-33/ SREBF2 with cholesterol homeostasis [74], [75], [77]. [score:4]
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[+] score: 8
Other miRNAs from this paper: mmu-mir-126a, mmu-mir-126b
Indeed, miR-499 expression is dissociated from that of its host gene MYH7b during myoblast differentiation due to a unique alternative splicing event which reduces MYH7b expression without modifying the level of miR-499. [score:5]
However, this uncoupling of expression between a microRNA and its host gene was already reported for miR-499 [19]. [score:3]
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[+] score: 7
Our data is in agreement with the report showing that overexpression of miR-499, which targets Sox6 and reduces its expression, resulted in a decrease in the Egr1 transcript level [113]. [score:7]
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[+] score: 7
In line with these results, we found that miR-208a-3p and miR-499-5p -both cardiac specific and highly abundant in the heart [23]- were either undetectable or very lowly expressed in the circulation of mice. [score:3]
Of the cardiac specific miRNAs, miR-208a-3p was not detectable in the plasma of ischemic heart failure mice and miR-499-5p showed the lowest miRNA expression levels in plasma compared to the other miRNAs (Fig 3 and S4 Table). [score:2]
In addition to the cardiac specific miR-208a-3p and miR-499-5p, we found that the expression of let-7i-5p, miR-16-5p, miR-27a-3p, miR-199a-3p and miR-223-3p was significantly higher in the heart compared to the kidney, independent of the presence of ischemic heart failure (S4 Fig and S5 Table). [score:2]
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[+] score: 7
Other miRNAs from this paper: hsa-let-7a-1, hsa-let-7a-2, hsa-let-7a-3, hsa-let-7b, hsa-let-7c, hsa-let-7d, hsa-let-7e, hsa-let-7f-1, hsa-let-7f-2, hsa-mir-17, hsa-mir-18a, hsa-mir-20a, hsa-mir-21, hsa-mir-22, hsa-mir-26a-1, hsa-mir-99a, hsa-mir-103a-2, hsa-mir-103a-1, hsa-mir-106a, hsa-mir-107, mmu-let-7g, mmu-let-7i, mmu-mir-99a, mmu-mir-101a, mmu-mir-125a, mmu-mir-125b-2, mmu-mir-126a, mmu-mir-127, mmu-mir-145a, mmu-mir-146a, mmu-mir-129-1, mmu-mir-206, hsa-mir-129-1, hsa-mir-148a, mmu-mir-122, mmu-mir-143, hsa-mir-139, hsa-mir-221, hsa-mir-222, hsa-mir-223, mmu-let-7d, mmu-mir-106a, hsa-let-7g, hsa-let-7i, hsa-mir-122, hsa-mir-125b-1, hsa-mir-143, hsa-mir-145, hsa-mir-125a, hsa-mir-125b-2, hsa-mir-126, hsa-mir-127, hsa-mir-129-2, hsa-mir-146a, hsa-mir-206, mmu-mir-148a, mmu-let-7a-1, mmu-let-7a-2, mmu-let-7b, mmu-let-7c-1, mmu-let-7c-2, mmu-let-7e, mmu-let-7f-1, mmu-let-7f-2, mmu-mir-18a, mmu-mir-20a, mmu-mir-21a, mmu-mir-22, mmu-mir-26a-1, mmu-mir-129-2, mmu-mir-103-1, mmu-mir-103-2, rno-let-7d, rno-mir-335, rno-mir-129-2, rno-mir-20a, mmu-mir-107, mmu-mir-17, mmu-mir-139, mmu-mir-223, mmu-mir-26a-2, mmu-mir-221, mmu-mir-222, mmu-mir-125b-1, hsa-mir-26a-2, hsa-mir-335, mmu-mir-335, rno-let-7a-1, rno-let-7a-2, rno-let-7b, rno-let-7c-1, rno-let-7c-2, rno-let-7e, rno-let-7f-1, rno-let-7f-2, rno-let-7i, rno-mir-17-1, rno-mir-18a, rno-mir-21, rno-mir-22, rno-mir-26a, rno-mir-99a, rno-mir-101a, rno-mir-103-2, rno-mir-103-1, rno-mir-107, rno-mir-122, rno-mir-125a, rno-mir-125b-1, rno-mir-125b-2, rno-mir-126a, rno-mir-127, rno-mir-129-1, rno-mir-139, rno-mir-143, rno-mir-145, rno-mir-146a, rno-mir-206, rno-mir-221, rno-mir-222, rno-mir-223, hsa-mir-196b, mmu-mir-196b, rno-mir-196b-1, hsa-mir-20b, hsa-mir-451a, mmu-mir-451a, rno-mir-451, hsa-mir-486-1, hsa-mir-499a, mmu-mir-486a, mmu-mir-20b, rno-mir-20b, rno-mir-499, mmu-mir-708, hsa-mir-708, rno-mir-17-2, rno-mir-708, hsa-mir-103b-1, hsa-mir-103b-2, mmu-mir-486b, rno-mir-126b, hsa-mir-451b, hsa-mir-499b, mmu-mir-145b, mmu-mir-21b, mmu-let-7j, mmu-mir-130c, mmu-mir-21c, mmu-mir-451b, mmu-let-7k, hsa-mir-486-2, mmu-mir-129b, mmu-mir-126b, rno-let-7g, rno-mir-148a, rno-mir-196b-2, rno-mir-486
After 6 and 12 wks of E [2] exposure, 15 miRNAs were down-regulated, e. g., miR-22, miR-99a, miR-106a, miR-127, miR-499, and 19 miRNAs were-up-regulated, e. g., miR-17-5p, miR-20a, miR-21, miR-129-3p, miR-106a, miR-22, and miR-127. [score:7]
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[+] score: 6
Encoded within the α- MHC gene, miR-208a directly regulates Myh7b and its intronic miRNA, miR-499 in the adult mouse heart. [score:3]
However, β -MHC, Myh7b and miR-499 expression were all unchanged in the Nrf2 deficient myocardium (data not presented). [score:3]
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[+] score: 6
The ISH demonstrated ubiquitous expression of both miRNAs throughout the epiblast and extraembryonic regions of the embryo (Figure 4B, 4C, 4E and 4F), while no signal was detected for the negative control miR-499-5p (Figure 4D), which is not expressed at this stage of development, confirming the specificity of staining. [score:6]
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[+] score: 6
However, aside from Wagner et al. [5] revealed an up-regulation of mir-371, mir-369-5p, mir-29c, mir-499 and let-7f upon in human replicative senescence, there was no reports for miRNA expression profiling of in aging process. [score:6]
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35
[+] score: 5
Furthermore myostatin expression is highest in type IIB fibres [12], is elevated in response to hind limb suspension and is a target for the type I fibre restricted microRNA, miR-499. [score:5]
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36
[+] score: 5
Notably, cardiac-specific miR-1, miR-133, miR-208 and miR-499 were all suppressed by two or more orders of magnitude [34], [35], as were the stemness and cell cycle repressors miR-141 and miR-137 [36]; in contrast, the proliferative miRNAs, miR-222 [37], increased dramatically in MDCs, and miR-221 was undetectable in myocytes but highly expressed in MDCs (Figure 5D). [score:5]
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[+] score: 5
SOX6 and PDCD4 enhance cardiomyocyte apoptosis through LPS -induced miR-499 inhibition. [score:3]
MiR-499-5p protects cardiomyocytes against ischaemic injury via anti-apoptosis by targeting PDCD4. [score:2]
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[+] score: 5
In this analysis, we observed that two miRNAsmiR-499-3p and miR-330-5p – were upregulated in cancer samples and followed the enrichment, suggesting they are key miRNAs in male breast cancer. [score:4]
miR-499-3p and miR-330-5p miRNA follow the enrichment, decreasing in the gynecomastia and increasing in the male breast cancer samples. [score:1]
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39
[+] score: 4
The expression level of miR-499 is similar to that of U6-snRNA. [score:3]
pri-mir499 forward: 5'-gcatgtgaacatcacagcaag-3', pri-mir499 reverse: 5'-ccaaacaccacctaagtcttc-3'. [score:1]
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40
[+] score: 4
Many miRNAs, such as miR-1, miR-133, miR-29, miR-214, miR-206, miR-486, miR-208b, and miR-499 were involved in the regulation of skeletal myogenesis by binding to its target genes 36, 37. [score:4]
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[+] score: 3
Corsten MF Circulating MicroRNA-208b and MicroRNA-499 reflect myocardial damage in cardiovascular diseaseCirc Cardiovasc Genet. [score:2]
Quantitative miRNA analysis was restricted to cardiomyocyte-enriched miRNAs: miR-1, miR-133a/b, miR-208a/b, and miR-499. [score:1]
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[+] score: 3
In addition to the finding that miRNAs as a whole are essential to proper muscle formation, individual miRNAs have been shown to play key roles in myogenesis, including species that regulate satellite cell quiescence (miR-489, [6]), promote proliferation (miR-133, miR-27 [7, 8]), promote myoblast differentiation (miR-206, miR-1, miR-486 [9– 11]), and regulate fiber type switching (miR-499, miR-208a, miR-208b [12]). [score:3]
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[+] score: 3
It has recently been shown that the expression of the myosin intronic microRNA (miR-499) in skeletal muscle powerfully induced the conversion from fast to a slower myofiber type [48]. [score:3]
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[+] score: 3
Other miRNAs from this paper: hsa-let-7a-1, hsa-let-7a-2, hsa-let-7a-3, hsa-let-7b, hsa-let-7c, hsa-let-7d, hsa-let-7e, hsa-let-7f-1, hsa-let-7f-2, hsa-mir-15a, hsa-mir-17, hsa-mir-19b-1, hsa-mir-19b-2, hsa-mir-23a, hsa-mir-24-1, hsa-mir-24-2, hsa-mir-25, hsa-mir-29a, hsa-mir-30a, hsa-mir-31, hsa-mir-32, hsa-mir-33a, hsa-mir-92a-1, hsa-mir-92a-2, hsa-mir-106a, mmu-let-7g, mmu-let-7i, mmu-mir-27b, mmu-mir-30a, mmu-mir-30b, mmu-mir-126a, mmu-mir-9-2, mmu-mir-135a-1, mmu-mir-137, mmu-mir-140, mmu-mir-150, mmu-mir-155, mmu-mir-24-1, mmu-mir-193a, mmu-mir-194-1, mmu-mir-204, mmu-mir-205, hsa-mir-30c-2, hsa-mir-30d, mmu-mir-143, mmu-mir-30e, hsa-mir-34a, hsa-mir-204, hsa-mir-205, hsa-mir-222, mmu-let-7d, mmu-mir-106a, mmu-mir-106b, hsa-let-7g, hsa-let-7i, hsa-mir-27b, hsa-mir-30b, hsa-mir-135a-1, hsa-mir-135a-2, hsa-mir-137, hsa-mir-140, hsa-mir-143, hsa-mir-9-1, hsa-mir-9-2, hsa-mir-9-3, hsa-mir-126, hsa-mir-150, hsa-mir-193a, hsa-mir-194-1, mmu-mir-19b-2, mmu-mir-30c-1, mmu-mir-30c-2, mmu-mir-30d, mmu-mir-200a, mmu-let-7a-1, mmu-let-7a-2, mmu-let-7b, mmu-let-7c-1, mmu-let-7c-2, mmu-let-7e, mmu-let-7f-1, mmu-let-7f-2, mmu-mir-15a, mmu-mir-23a, mmu-mir-24-2, mmu-mir-29a, mmu-mir-31, mmu-mir-92a-2, mmu-mir-34a, rno-mir-322-1, mmu-mir-322, rno-let-7d, rno-mir-329, mmu-mir-329, rno-mir-140, rno-mir-350-1, mmu-mir-350, hsa-mir-200c, hsa-mir-155, mmu-mir-17, mmu-mir-25, mmu-mir-32, mmu-mir-200c, mmu-mir-33, mmu-mir-222, mmu-mir-135a-2, mmu-mir-19b-1, mmu-mir-92a-1, mmu-mir-9-1, mmu-mir-9-3, mmu-mir-7b, hsa-mir-194-2, mmu-mir-194-2, hsa-mir-106b, hsa-mir-30c-1, hsa-mir-200a, hsa-mir-30e, hsa-mir-375, mmu-mir-375, mmu-mir-133b, hsa-mir-133b, rno-let-7a-1, rno-let-7a-2, rno-let-7b, rno-let-7c-1, rno-let-7c-2, rno-let-7e, rno-let-7f-1, rno-let-7f-2, rno-let-7i, rno-mir-7b, rno-mir-9a-1, rno-mir-9a-3, rno-mir-9a-2, rno-mir-17-1, rno-mir-19b-1, rno-mir-19b-2, rno-mir-23a, rno-mir-24-1, rno-mir-24-2, rno-mir-25, rno-mir-27b, rno-mir-29a, rno-mir-30c-1, rno-mir-30e, rno-mir-30b, rno-mir-30d, rno-mir-30a, rno-mir-30c-2, rno-mir-31a, rno-mir-32, rno-mir-33, rno-mir-34a, rno-mir-92a-1, rno-mir-92a-2, rno-mir-106b, rno-mir-126a, rno-mir-135a, rno-mir-137, rno-mir-143, rno-mir-150, rno-mir-193a, rno-mir-194-1, rno-mir-194-2, rno-mir-200c, rno-mir-200a, rno-mir-204, rno-mir-205, rno-mir-222, hsa-mir-196b, mmu-mir-196b, rno-mir-196b-1, mmu-mir-410, hsa-mir-329-1, hsa-mir-329-2, mmu-mir-470, hsa-mir-410, hsa-mir-486-1, hsa-mir-499a, rno-mir-133b, mmu-mir-486a, hsa-mir-33b, rno-mir-499, mmu-mir-467d, hsa-mir-891a, hsa-mir-892a, hsa-mir-890, hsa-mir-891b, hsa-mir-888, hsa-mir-892b, rno-mir-17-2, rno-mir-375, rno-mir-410, mmu-mir-486b, rno-mir-31b, rno-mir-9b-3, rno-mir-9b-1, rno-mir-126b, rno-mir-9b-2, hsa-mir-499b, mmu-let-7j, mmu-mir-30f, mmu-let-7k, hsa-mir-486-2, mmu-mir-126b, rno-mir-155, rno-let-7g, rno-mir-15a, rno-mir-196b-2, rno-mir-322-2, rno-mir-350-2, rno-mir-486, mmu-mir-9b-2, mmu-mir-9b-1, mmu-mir-9b-3
Similarly, miR-133b, miR-137, miR-155, and miR499 were exclusively expressed in the caudal region of the mouse epididymis but were wi dely distributed throughout the rat and/or human epididymis (S4 Table). [score:3]
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[+] score: 3
It was reported that in cardiac progenitor cells, the over -expression of miR1 and miR499 reduced the rate of cell proliferation and enhanced the differentiation via repressing the HDAC4 or Sox6 [8]. [score:3]
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[+] score: 3
qRT-PCRwas conducted for miRs that had been previously described to be involved in pathological cardiac hypertrophy(miR-21 and miR-195) and in mo dels of cardiovascular disease associated with cardiomyocyte injury (miR-499). [score:3]
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47
[+] score: 3
Other miRNAs from this paper: hsa-mir-499a, mmu-mir-208b, hsa-mir-208b, hsa-mir-499b
However, unlike Myh7 which was hypermethylated, regions within the promoter for both miR-208b and miR499 were hypomethylated. [score:1]
Of the miRNA promoter regions with DMRs, two were related to cardiac hypertrophy including miR-208b and miR-499 (Table 8) [49], [50]. [score:1]
MiR-208b is located within intron 31 of the Myh7 gene which is also differentially methylated and miR-499 is located in intron 19 of Myh7b. [score:1]
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48
[+] score: 3
Some of these microRNAs that exhibit specific patterns of muscle expression are dubbed “myomiRs”; these include members of the bicistronic miR-1/133a and miR206/133b families [20], and a group of microRNAs, namely miR-208, miR-208b, and miR-499, that are embedded in genes encoding the myosin heavy chain [21]. [score:3]
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49
[+] score: 2
Xiao et al demonstrated that serum miR-208a and miR-499 were elevated after AMI and might be potential biomarkers for AMI [47]. [score:1]
Circ Cardiovasc Genet [Epub ahead of print] 47 Xiao J, Shen B, Li J, Lv D, Zhao Y, et al (2014) Serum microRNA-499 and microRNA-208a as biomarkers of acute myocardial infarction. [score:1]
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[+] score: 2
An increasing number of miRNAs with different functions in heart development have also been identified, including miR-1, miR-208, miR-133, miR-206, miR-126, miR-143, miR-145, and miR-499; from this group, we analyzed the 7 miRNAs most relevant to postnatal heart growth. [score:2]
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51
[+] score: 2
Other miRNAs from this paper: hsa-let-7a-1, hsa-let-7a-2, hsa-let-7a-3, hsa-let-7b, hsa-let-7c, hsa-let-7d, hsa-let-7e, hsa-let-7f-1, hsa-let-7f-2, hsa-mir-15a, hsa-mir-26b, hsa-mir-29a, hsa-mir-30a, hsa-mir-29b-1, hsa-mir-29b-2, hsa-mir-106a, mmu-let-7g, mmu-let-7i, mmu-mir-15b, mmu-mir-29b-1, mmu-mir-30a, mmu-mir-30b, mmu-mir-125a, mmu-mir-125b-2, mmu-mir-130a, mmu-mir-138-2, mmu-mir-181a-2, mmu-mir-182, hsa-mir-30c-2, hsa-mir-30d, mmu-mir-30e, hsa-mir-10a, hsa-mir-34a, hsa-mir-181a-2, hsa-mir-181b-1, hsa-mir-181c, hsa-mir-182, hsa-mir-181a-1, mmu-mir-297a-1, mmu-mir-297a-2, mmu-mir-301a, mmu-mir-34c, mmu-mir-34b, mmu-let-7d, mmu-mir-106a, mmu-mir-106b, hsa-let-7g, hsa-let-7i, hsa-mir-15b, hsa-mir-30b, hsa-mir-125b-1, hsa-mir-130a, hsa-mir-138-2, hsa-mir-125a, hsa-mir-125b-2, hsa-mir-138-1, mmu-mir-30c-1, mmu-mir-30c-2, mmu-mir-30d, mmu-let-7a-1, mmu-let-7a-2, mmu-let-7b, mmu-let-7c-1, mmu-let-7c-2, mmu-let-7e, mmu-let-7f-1, mmu-let-7f-2, mmu-mir-15a, mmu-mir-26b, mmu-mir-29a, mmu-mir-29c, mmu-mir-34a, rno-mir-301a, rno-let-7d, rno-mir-344a-1, mmu-mir-344-1, rno-mir-346, mmu-mir-346, rno-mir-352, hsa-mir-181b-2, mmu-mir-10a, mmu-mir-181a-1, mmu-mir-29b-2, mmu-mir-138-1, mmu-mir-181b-1, mmu-mir-181c, mmu-mir-125b-1, hsa-mir-106b, hsa-mir-29c, hsa-mir-30c-1, hsa-mir-34b, hsa-mir-34c, hsa-mir-301a, hsa-mir-30e, hsa-mir-362, mmu-mir-362, hsa-mir-369, hsa-mir-374a, mmu-mir-181b-2, hsa-mir-346, rno-let-7a-1, rno-let-7a-2, rno-let-7b, rno-let-7c-1, rno-let-7c-2, rno-let-7e, rno-let-7f-1, rno-let-7f-2, rno-let-7i, rno-mir-10a, rno-mir-15b, rno-mir-26b, rno-mir-29b-2, rno-mir-29a, rno-mir-29b-1, rno-mir-29c-1, rno-mir-30c-1, rno-mir-30e, rno-mir-30b, rno-mir-30d, rno-mir-30a, rno-mir-30c-2, rno-mir-34b, rno-mir-34c, rno-mir-34a, rno-mir-106b, rno-mir-125a, rno-mir-125b-1, rno-mir-125b-2, rno-mir-130a, rno-mir-138-2, rno-mir-138-1, rno-mir-181c, rno-mir-181a-2, rno-mir-181b-1, rno-mir-181b-2, rno-mir-181a-1, hsa-mir-449a, mmu-mir-449a, rno-mir-449a, mmu-mir-463, mmu-mir-466a, hsa-mir-483, hsa-mir-493, hsa-mir-181d, hsa-mir-499a, hsa-mir-504, mmu-mir-483, rno-mir-483, mmu-mir-369, rno-mir-493, rno-mir-369, rno-mir-374, hsa-mir-579, hsa-mir-582, hsa-mir-615, hsa-mir-652, hsa-mir-449b, rno-mir-499, hsa-mir-767, hsa-mir-449c, hsa-mir-762, mmu-mir-301b, mmu-mir-374b, mmu-mir-762, mmu-mir-344d-3, mmu-mir-344d-1, mmu-mir-673, mmu-mir-344d-2, mmu-mir-449c, mmu-mir-692-1, mmu-mir-692-2, mmu-mir-669b, mmu-mir-652, mmu-mir-615, mmu-mir-804, mmu-mir-181d, mmu-mir-879, mmu-mir-297a-3, mmu-mir-297a-4, mmu-mir-344-2, mmu-mir-466b-1, mmu-mir-466b-2, mmu-mir-466b-3, mmu-mir-466c-1, mmu-mir-466e, mmu-mir-466f-1, mmu-mir-466f-2, mmu-mir-466f-3, mmu-mir-466g, mmu-mir-466h, mmu-mir-493, mmu-mir-504, mmu-mir-466d, mmu-mir-449b, hsa-mir-374b, hsa-mir-301b, rno-mir-466b-1, rno-mir-466b-2, rno-mir-466c, rno-mir-879, mmu-mir-582, rno-mir-181d, rno-mir-182, rno-mir-301b, rno-mir-463, rno-mir-673, rno-mir-652, mmu-mir-466l, mmu-mir-669k, mmu-mir-466i, mmu-mir-669i, mmu-mir-669h, mmu-mir-466f-4, mmu-mir-466k, mmu-mir-466j, mmu-mir-1193, mmu-mir-767, rno-mir-362, rno-mir-504, rno-mir-582, rno-mir-615, mmu-mir-3080, mmu-mir-466m, mmu-mir-466o, mmu-mir-466c-2, mmu-mir-466b-4, mmu-mir-466b-5, mmu-mir-466b-6, mmu-mir-466b-7, mmu-mir-466p, mmu-mir-466n, mmu-mir-344e, mmu-mir-344b, mmu-mir-344c, mmu-mir-344g, mmu-mir-344f, mmu-mir-374c, mmu-mir-466b-8, hsa-mir-466, hsa-mir-1193, rno-mir-449c, rno-mir-344b-2, rno-mir-466d, rno-mir-344a-2, rno-mir-1193, rno-mir-344b-1, hsa-mir-374c, hsa-mir-499b, mmu-mir-466q, mmu-mir-344h-1, mmu-mir-344h-2, mmu-mir-344i, rno-mir-344i, rno-mir-344g, mmu-let-7j, mmu-mir-30f, mmu-let-7k, mmu-mir-692-3, rno-let-7g, rno-mir-15a, rno-mir-762, mmu-mir-466c-3, rno-mir-29c-2, rno-mir-29b-3, rno-mir-344b-3, rno-mir-466b-3, rno-mir-466b-4
The identity, fold-change variation, direction of alteration, and biological function of these miRNAs are reported in Table 2. In mice bearing adenomas, 5 miRNAs (miR-34b, miR-106a, miR-499, miR-466, and miR-493) were altered in the blood serum but not in lung. [score:2]
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52
[+] score: 2
Functional SNPs can occur in mature miRNAs outside the seed region, as recently demonstrated by the finding of a rare variant at nt 17 of miR-499 [27]. [score:1]
Evaluation of the effects of this variant in transgenic mice showed that it protected against the cardiomyopathy that developed with overexpression of the wildtype form of miR-499. [score:1]
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[+] score: 2
Other miRNAs from this paper: gga-mir-499
An advantage of splicing -based NMD as a mechanism for regulating MYH7B levels is that it enables the cell to separate steady state levels of MYH7B protein from transcription of the MYH7B gene, which also hosts a microRNA, miR-499, within one of its introns [67]. [score:2]
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54
[+] score: 1
Circulating miRNAs like miR-1, miR-133a and miR-499 are promising biomarkers for the diagnosis of acute myocardial infarction (8, 9). [score:1]
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55
[+] score: 1
The latter is supported by the observation that the two known miRNAs involved in fast-to-slow fiber programs, miR-208b and miR-499 [48], were not affected in SOD1-G93A mo del (although miR-208b was found to be slow-twitch enriched in both mutant and control animals, Tables S3 and S4). [score:1]
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56
[+] score: 1
Among them, miR-1, miR-133, miR-206, miR-208 and miR-499 have been described as muscle specific miRNAs, or myomiRs [6, 13]. [score:1]
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57
[+] score: 1
Among miRNAs expressed in the heart, miR-1, miR-133, miR-208, and miR-499 are the most commonly investigated subtypes. [score:1]
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58
[+] score: 1
Other miRNAs from this paper: mmu-mir-146a, mmu-mir-122, mmu-mir-96, mmu-mir-717
SNPs in hsa-miR-3117-3p and -4467 matched two different seed regions of hsa-miR-499-5p and -885-3p, respectively (Figure S1). [score:1]
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59
[+] score: 1
A group of miRNAs, highly enriched in skeletal muscle (referred to as myomiRs), has recently been identified and includes miR-1, miR-133a, miR-133b, miR-206, miR-208, miR-208b, miR-486, and miR-499 [33– 37]. [score:1]
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60
[+] score: 1
Several miRNAs have been found to participate in the pathogenesis of CRC, including miR-21, miR-451, miR-499-5p, miR-375, and miR-142-5p [8]. [score:1]
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61
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miR-499 promotes differentiation of CPCs into cardiomyocytes [12]. [score:1]
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62
[+] score: 1
Additionally, miR-23a [15], miR-24 [16], miR-26 [17], miR-27a [18, 19], miR-27b [20], miR-29 [21], miR-124 [22], miR-128a [23], miR-146b [24], miR-148a [25], miR-155 [26], miR-181 [27], miR-199 [28], miR-186 [29], miR-214 [30], miR-221/222 [31], miR-351 [32], miR-486 [33], miR-489 [34], miR-499 [35] and miR-3906 [36] are reported to be involved in skeletal myogenesis. [score:1]
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63
[+] score: 1
A substantial number of miRNA including miR-1 [12], miR-15 [13], miR-21 [14], [15], miR-24 [16], [17], [18], miR-499 [19], and the miR-17-92 family [20], miR-124 [21], miR-15a/b [22] (2012), miR-93 [23], miR-29 family [24], [25], miR-146a [26], [27], miR-145/451 [28], miR-384-5p [29], miR-424 [30], and miR-494 [31] have been identified in I/R injury. [score:1]
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64
[+] score: 1
Other miRNAs from this paper: hsa-let-7a-1, hsa-let-7a-2, hsa-let-7a-3, hsa-let-7b, hsa-let-7c, hsa-let-7d, hsa-let-7e, hsa-let-7f-1, hsa-let-7f-2, hsa-mir-26a-1, hsa-mir-26b, hsa-mir-27a, hsa-mir-29a, hsa-mir-32, hsa-mir-33a, hsa-mir-99a, hsa-mir-103a-2, hsa-mir-103a-1, hsa-mir-107, mmu-let-7g, mmu-let-7i, mmu-mir-15b, mmu-mir-99a, mmu-mir-126a, mmu-mir-128-1, mmu-mir-130a, mmu-mir-140, mmu-mir-154, mmu-mir-204, mmu-mir-143, hsa-mir-204, hsa-mir-211, hsa-mir-218-1, hsa-mir-218-2, hsa-mir-222, hsa-mir-223, mmu-mir-301a, mmu-mir-34c, mmu-mir-34b, mmu-let-7d, hsa-let-7g, hsa-let-7i, hsa-mir-15b, hsa-mir-128-1, hsa-mir-130a, hsa-mir-140, hsa-mir-143, hsa-mir-126, hsa-mir-129-2, hsa-mir-154, mmu-let-7a-1, mmu-let-7a-2, mmu-let-7b, mmu-let-7c-1, mmu-let-7c-2, mmu-let-7e, mmu-let-7f-1, mmu-let-7f-2, mmu-mir-26a-1, mmu-mir-26b, mmu-mir-29a, mmu-mir-29c, mmu-mir-27a, mmu-mir-129-2, mmu-mir-103-1, mmu-mir-103-2, mmu-mir-340, mmu-mir-107, mmu-mir-32, mmu-mir-218-1, mmu-mir-218-2, mmu-mir-223, mmu-mir-26a-2, mmu-mir-211, mmu-mir-222, mmu-mir-128-2, hsa-mir-128-2, hsa-mir-29c, hsa-mir-101-2, hsa-mir-34b, hsa-mir-34c, hsa-mir-301a, hsa-mir-26a-2, hsa-mir-379, mmu-mir-379, hsa-mir-340, mmu-mir-409, hsa-mir-409, hsa-mir-499a, hsa-mir-455, hsa-mir-670, mmu-mir-1249, mmu-mir-670, mmu-mir-455, bta-mir-26a-2, bta-mir-29a, bta-let-7f-2, bta-mir-101-2, bta-mir-103-1, bta-mir-16b, bta-mir-222, bta-mir-26b, bta-mir-27a, bta-mir-499, bta-mir-99a, bta-mir-126, bta-mir-128-1, bta-mir-34b, bta-mir-107, bta-mir-140, bta-mir-15b, bta-mir-218-2, bta-let-7d, bta-mir-29c, bta-mir-455, bta-let-7g, bta-let-7a-1, bta-let-7f-1, bta-let-7i, bta-mir-34c, bta-let-7a-2, bta-let-7a-3, bta-let-7b, bta-let-7c, bta-let-7e, bta-mir-103-2, bta-mir-204, hsa-mir-1249, hsa-mir-1306, hsa-mir-103b-1, hsa-mir-103b-2, bta-mir-128-2, bta-mir-129-2, bta-mir-130a, bta-mir-143, bta-mir-154a, bta-mir-211, bta-mir-218-1, bta-mir-223, bta-mir-26a-1, bta-mir-301a, bta-mir-32, bta-mir-33a, bta-mir-340, bta-mir-379, bta-mir-409a, bta-mir-670, mmu-mir-1306, bta-mir-1306, bta-mir-1249, bta-mir-2284i, bta-mir-2285a, bta-mir-2284s, bta-mir-2285d, bta-mir-2284l, bta-mir-2284j, bta-mir-2284t, bta-mir-2285b-1, bta-mir-2284d, bta-mir-2284n, bta-mir-2284g, bta-mir-2284p, bta-mir-2284u, bta-mir-2284f, bta-mir-2284a, bta-mir-2284k, bta-mir-2284c, bta-mir-2284v, bta-mir-2285c, bta-mir-2284q, bta-mir-2284m, bta-mir-2284b, bta-mir-2284r, bta-mir-2284h, bta-mir-2284o, bta-mir-2284e, hsa-mir-1260b, bta-mir-2284w, bta-mir-2284x, bta-mir-409b, hsa-mir-499b, bta-mir-1260b, bta-mir-2284y-1, bta-mir-2285e-1, bta-mir-2285e-2, bta-mir-2285f-1, bta-mir-2285f-2, bta-mir-2285g-1, bta-mir-2285h, bta-mir-2285i, bta-mir-2285j-1, bta-mir-2285j-2, bta-mir-2285k-1, bta-mir-2285l, bta-mir-6119, mmu-let-7j, bta-mir-2285o-1, bta-mir-2285o-2, bta-mir-2285n-1, bta-mir-2285n-2, bta-mir-2285p, bta-mir-2285m-1, bta-mir-2285m-2, bta-mir-2284y-2, bta-mir-2285n-3, bta-mir-2285n-4, bta-mir-2284y-3, bta-mir-154c, bta-mir-154b, bta-mir-2285o-3, bta-mir-2285o-4, bta-mir-2285m-3, bta-mir-2284y-4, bta-mir-2284y-5, bta-mir-2284y-6, bta-mir-2285m-4, bta-mir-2285o-5, bta-mir-2285m-5, bta-mir-2285n-5, bta-mir-2285n-6, bta-mir-2284y-7, bta-mir-2285n-7, bta-mir-2284z-1, bta-mir-2284aa-1, bta-mir-2285k-2, bta-mir-2284z-3, bta-mir-2284aa-2, bta-mir-2284aa-3, bta-mir-2285k-3, bta-mir-2285k-4, bta-mir-2284z-4, bta-mir-2285k-5, bta-mir-2284z-5, bta-mir-2284z-6, bta-mir-2284z-7, bta-mir-2284aa-4, bta-mir-2285q, bta-mir-2285r, bta-mir-2285s, bta-mir-2285t, bta-mir-2285b-2, bta-mir-2285v, bta-mir-2284z-2, mmu-let-7k, mmu-mir-126b, bta-mir-2285g-2, bta-mir-2285g-3, bta-mir-2285af-1, bta-mir-2285af-2, bta-mir-2285y, bta-mir-2285w, bta-mir-2285x, bta-mir-2285z, bta-mir-2285u, bta-mir-2285aa, bta-mir-2285ab, bta-mir-2284ab, bta-mir-2285ac, bta-mir-2285ad, bta-mir-2284ac, bta-mir-2285ae, chi-let-7a, chi-let-7b, chi-let-7c, chi-let-7d, chi-let-7e, chi-let-7f, chi-let-7g, chi-let-7i, chi-mir-103, chi-mir-107, chi-mir-1249, chi-mir-126, chi-mir-1306, chi-mir-130a, chi-mir-140, chi-mir-143, chi-mir-154a, chi-mir-154b, chi-mir-15b, chi-mir-16b, chi-mir-204, chi-mir-211, chi-mir-222, chi-mir-223, chi-mir-2284a, chi-mir-2284b, chi-mir-2284c, chi-mir-2284d, chi-mir-2284e, chi-mir-26a, chi-mir-26b, chi-mir-27a, chi-mir-29a, chi-mir-29c, chi-mir-301a, chi-mir-33a, chi-mir-340, chi-mir-34b, chi-mir-34c, chi-mir-379, chi-mir-409, chi-mir-455, chi-mir-499, chi-mir-99a, bta-mir-2285ag, bta-mir-2285ah, bta-mir-2285ai, bta-mir-2285aj, bta-mir-2285ak, bta-mir-2285al, bta-mir-2285am, bta-mir-2285ar, bta-mir-2285as-1, bta-mir-2285as-2, bta-mir-2285as-3, bta-mir-2285at-1, bta-mir-2285at-2, bta-mir-2285at-3, bta-mir-2285at-4, bta-mir-2285au, bta-mir-2285av, bta-mir-2285aw, bta-mir-2285ax-1, bta-mir-2285ax-2, bta-mir-2285ax-3, bta-mir-2285ay, bta-mir-2285az, bta-mir-2285an, bta-mir-2285ao-1, bta-mir-2285ao-2, bta-mir-2285ap, bta-mir-2285ao-3, bta-mir-2285aq-1, bta-mir-2285aq-2, bta-mir-2285ba-1, bta-mir-2285ba-2, bta-mir-2285bb, bta-mir-2285bc, bta-mir-2285bd, bta-mir-2285be, bta-mir-2285bf-1, bta-mir-2285bf-2, bta-mir-2285bf-3, bta-mir-2285bg, bta-mir-2285bh, bta-mir-2285bi-1, bta-mir-2285bi-2, bta-mir-2285bj-1, bta-mir-2285bj-2, bta-mir-2285bk, bta-mir-2285bl, bta-mir-2285bm, bta-mir-2285bn, bta-mir-2285bo, bta-mir-2285bp, bta-mir-2285bq, bta-mir-2285br, bta-mir-2285bs, bta-mir-2285bt, bta-mir-2285bu-1, bta-mir-2285bu-2, bta-mir-2285bv, bta-mir-2285bw, bta-mir-2285bx, bta-mir-2285by, bta-mir-2285bz, bta-mir-2285ca, bta-mir-2285cb, bta-mir-2285cc, bta-mir-2285cd, bta-mir-2285ce, bta-mir-2285cf, bta-mir-2285cg, bta-mir-2285ch, bta-mir-2285ci, bta-mir-2285cj, bta-mir-2285ck, bta-mir-2285cl, bta-mir-2285cm, bta-mir-2285cn, bta-mir-2285co, bta-mir-2285cp, bta-mir-2285cq, bta-mir-2285cr-1, bta-mir-2285cr-2, bta-mir-2285cs, bta-mir-2285ct, bta-mir-2285cu, bta-mir-2285cv-1, bta-mir-2285cv-2, bta-mir-2285cw-1, bta-mir-2285cw-2, bta-mir-2285cx, bta-mir-2285cy, bta-mir-2285cz, bta-mir-2285da, bta-mir-2285db, bta-mir-2285dc, bta-mir-2285dd, bta-mir-2285de, bta-mir-2285df, bta-mir-2285dg, bta-mir-2285dh, bta-mir-2285di, bta-mir-2285dj, bta-mir-2285dk, bta-mir-2285dl-1, bta-mir-2285dl-2, bta-mir-2285dm
Among the seven other conserved intragenic precursors in human, mouse and cow, mir-1249 in the host gene KIAA0930 and mir-499 in the host gene MYH7B (Myosin heavy chain 7B cardiac muscle beta) were not retrieved either in the goat protein-coding genes available, suggesting once again that these genes have yet to be described in the goat genome. [score:1]
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MiR-499 was shown to promote ventricular specification; miR-1 facilitates electrophysiological maturation (Fu et al., 2011). [score:1]
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66
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Elevated miR-499 levels blunt the cardiac stress response. [score:1]
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