Loss of MicroRNA-155 Protects the Heart From Pathological Cardiac HypertrophyNovelty and Significance
Rationale: In response to mechanical and pathological stress, adult mammalian hearts often undergo mal-remodeling, a process commonly characterized as pathological hypertrophy, which is associated with upregulation of fetal genes, increased fibrosis, and reduction of cardiac dysfunction. The molecular pathways that regulate this process are not fully understood.
Objective: To explore the function of microRNA-155 (miR-155) in cardiac hypertrophy and remodeling.
Methods and Results: Our previous work identified miR-155 as a critical microRNA that repressed the expression and function of the myocyte enhancer factor 2A. In this study, we found that miR-155 is expressed in cardiomyocytes and that its expression is reduced in pressure overload–induced hypertrophic hearts. In mouse models of cardiac hypertrophy, miR-155 null hearts suppressed cardiac hypertrophy and cardiac remodeling in response to 2 independent pathological stressors, transverse aortic restriction and an activated calcineurin transgene. Most importantly, loss of miR-155 prevents the progress of heart failure and substantially extends the survival of calcineurin transgenic mice. The function of miR-155 in hypertrophy is confirmed in isolated cardiomyocytes. We identified jumonji, AT rich interactive domain 2 (Jarid2) as an miR-155 target in the heart. miR-155 directly represses Jarid2, whose expression is increased in miR-155 null hearts. Inhibition of endogenous Jarid2 partially rescues the effect of miR-155 loss in isolated cardiomyocytes.
Conclusions: Our studies uncover miR-155 as an inducer of pathological cardiomyocyte hypertrophy and suggest that inhibition of endogenous miR-155 might have clinical potential to suppress cardiac hypertrophy and heart failure.
The adult heart is primarily composed of terminally differentiated, mature cardiomyocytes that express signature genes related to contraction. In response to physiological, mechanical, or pathological stress, the heart undergoes hypertrophic growth, anatomically defined as an increase in the size of cardiomyocytes without an increase in cell number.1,2 Pressure overload–induced cardiac hypertrophy is initially an adaptive response to maintain cardiac output. However, prolonged hypertrophic growth is associated with adverse consequences that often lead to heart failure and sudden death.1–4
MicroRNAs (miRNAs) are a class of small noncoding RNAs that modulate gene expression at the post-transcriptional level. Recent functional studies using both gain- and loss-of-function approaches in mice have started to uncover the important roles of miRNAs in cardiac hypertrophy and remodeling.5–7 We showed that microRNA-22 (miR-22) protects the heart from stress-induced cardiac remodeling,8 whereas the miR-17-92 cluster is a potent regulator of cardiomyocyte proliferation and cardiac regeneration.9 miR-155 is encoded and coexpressed from the noncoding RNA gene BIC, and it is highly expressed in activated B and T cells and in monocytes/macrophages.10 Genetic studies in mouse models have demonstrated that miR-155 plays a vital role in hematopoiesis, lymphocyte homeostasis, and tolerance.10–12 In the cardiovascular system, miR-155 was reported to be expressed in atherosclerotic plaques and proinflammatory macrophages. miR-155 knockout mice displayed reduced plaque size after partial carotid ligation in atherosclerotic (apolipoprotein E–deficient) mice, suggesting a role of miR-155 in atherosclerosis.13 In another study, overexpression of miR-155 in human cardiomyocyte progenitor cells was linked to protection from necrotic cell death in vitro.14 Furthermore, it was reported that inhibition of endogenous miR-155 attenuated cardiac infiltration by monocyte macrophages.15 Most recently, the in vivo function of miR-155 in cardiomyocyte hypertrophy was reported.16
Previously, we examined the post-transcriptional regulation of the myocyte enhancer factor 2A (MEF2A) gene and reported that miR-155 represses the expression and function of MEF2A in myocytes.17 Here, we study the function of miR-155 in the heart, and we report that miR-155 is expressed in cardiomyocytes and its expression is dynamically regulated during cardiac hypertrophy. We show that genetic deletion of miR-155 prevents cardiac hypertrophy induced by pressure overload and the calcineurin transgene. Furthermore, inhibition of miR-155 in isolated cardiomyocytes diminishes agonist-induced cardiomyocyte hypertrophy. We identified Jarid2 as an miR-155 target in the hypertrophy pathway.
Cell culture, quantitative reverse transcriptase polymerase chain reaction (qPCR), Western blot analyses, and immunochemistry were performed according to routine protocols. miR-155 mutant mice and calcineurin transgenic mice (Tg(Myh6-Ppp3ca)37Eno), which were originally generated by Drs Molkentin and Olson, were obtained from The Jackson Laboratory. The transverse aortic constriction (TAC) operation and measurement of cardiac function by echocardiography are described.8,9
Values are reported as means±SEM unless indicated otherwise. The 2-tailed Mann–Whitney U test was used for comparing 2 means (Prism, GraphPad). Values of P<0.05 were considered statistically significant.
MiR-155 Is Expressed in Cardiomyocytes and Its Expression Is Reduced in Hypertrophic Hearts
In a prior study, we identified miR-155 as a key miRNA that repressed the expression of MEF2A, and we reported that miR-155 repressed C2C12 skeletal muscle myoblast differentiation, at least in part, by repressing MEF2A.17 Numerous studies have documented that miR-155 is ubiquitously expressed in adult mouse tissues and enriched in lymphocytes and macrophages.10,12,15,16 We examined the expression of miR-155 in the hearts of fetal, postnatal, and adult mice. qPCR analyses showed that the expression of miR-155 was relatively low in embryonic and neonatal hearts. However, miR-155 expression was increased in postnatal day 7 and adult hearts, with the highest miR-155 expression detected in the hearts of 15-month-old mice (Figure 1A). These data suggest that miR-155 may play an important role in the adult heart and cardiac remodeling.
Next, we examined the distribution of miR-155 expression in cardiomyocyte and noncardiomyocyte fractions of the adult heart. We found that miR-155 expression is enriched in cardiomyocytes of adult hearts (Figure 1B). For positive controls, we showed that expression of the cardiomyocyte-specific genes cardiac troponin T and miR-18 is enriched in the cardiomyocyte fraction. In contrast, expression of periostin, which marks cardiac epithelial cells,18 was restricted to the noncardiomyocyte fraction (Figure 1B).
We next asked whether the expression of miR-155 is altered in cardiac hypertrophy. miR-155 expression was reduced in cardiac hypertrophy induced by pressure overload via TAC at 2 and 4 weeks8,9 (Figure 1C), which is consistent with a prior report.19 However, miR-155 expression was not altered in the hypertrophic heart of calcineurin transgenic mice (Figure 1C). Together, these data demonstrate that miR-155 is expressed in cardiomyocytes of adult hearts and that its expression is regulated in hypertrophic hearts.
MiR-155 Is Required for Pressure Overload–Induced Cardiac Hypertrophy and Remodeling
To study the function of miR-155 in the heart, we examined miR-155 knockout mice. miR-155 null mice were viable and fertile as previously reported.11,20 We verified that no miR-155 expression was detectable in tissues of miR-155 mutant mice using sensitive qPCR assays (data not shown). The gross morphology and the heart weight/body weight ratio of miR-155 mutant mice did not differ from that of wild-type littermate controls. Histological examination and Sirius red/fast green staining did not reveal abnormal cardiac morphology or fibrosis in miR-155 mutant mice. Echocardiographic measures of left ventricular (LV) size and cardiac function (as documented as fractional shortening) did not reveal any differences between miR-155 mutant mice and their littermate controls (Online Tables I and II). Together, these studies indicate that miR-155 is dispensable for normal mouse development and cardiac function under physiological conditions.
Next, we tested whether miR-155 plays a role in stress-dependent cardiac response and remodeling. We tested the functional involvement of miR-155 in cardiac hypertrophy after pressure overload induced by TAC, a widely used animal model for cardiac hypertrophy.2 TAC induced massive cardiac hypertrophy in wild-type mice, evidenced by an increase in heart size. However, heart size of miR-155 null mice was substantially smaller than that of the control wild-type mice after TAC (Figure 2A). The development of cardiac hypertrophy in the hearts of wild-type mice and the repression of hypertrophic growth in miR-155 null mice under the TAC condition are supported by calculating heart weight/body weight ratio (Figure 2B). Histological analysis further confirmed the lack of increase in ventricle wall thickness in miR-155 null mice in response to TAC, whereas TAC-induced hypertrophy was obvious in ventricles of control mice (Figure 2C). At the cellular level, TAC significantly increased the size of cardiomyocytes in wild-type control hearts. Loss of miR-155 substantially eliminated the increase in cardiomyocyte size (Figure 2D and 2E). TAC also increased cardiac fibrosis at 4 weeks, consistent with a prior report.21 However, cardiac fibrosis was substantially suppressed in the hearts of miR-155-knockout mice (Figure 2F).
We performed echocardiography measurements to document cardiac function at different time points (2 and 4 weeks) after TAC. There was a dramatic increase in the thickness of the LV posterior wall and the interventricular septum in wild-type control mice after TAC surgery. This hypertrophic response was significantly reduced in miR-155 mutant hearts (Online Tables I and II), indicating that loss of miR-155 reduced TAC-induced cardiac hypertrophy. Furthermore, increases in LV internal dimension and volume were substantially mitigated in miR-155 null hearts after TAC (Online Tables I and II), indicating that loss of miR-155 suppressed the development of cardiac hypertrophy and the progression of dilated cardiomyopathy. These observations are consistent with the results of gross cardiac morphology and histology. Functionally, we found that miR-155-knockout hearts preserve ventricular systolic function under pressure overload, as evidenced by the substantially higher fractional shortening in hearts of miR-155-knockout mice compared with wild-type controls (Figure 2G; Online Tables I and II).
We examined the expression of hypertrophic markers in miR-155-knockout and control mice after TAC. TAC-mediated induction of brain natriuretic peptide and β-myosin heavy chain (β-MHC) expression, as measured by qPCR assays, was suppressed in the hearts of miR-155 mutant mice (Figure 2H). In addition, we confirmed that expression of β-MHC protein, induced by TAC in the hearts of control wild-type mice, was markedly reduced in the hearts of miR-155 mutant mice (Figure 2I). Together, these data demonstrate that miR-155 loss-of-function protects the heart from developing pathological cardiac hypertrophy in the face of cardiac stress.
Loss of MiR-155 Suppresses Calcineurin-Induced Cardiac Hypertrophy and Heart Failure
Calcineurin is a calcium-regulated phosphatase, and previous studies have shown that cardiac-specific overexpression of calcineurin in α-MHC-calcineurin transgenic mice induces striking cardiac hypertrophy.22 To test whether miR-155 is involved in calcineurin-induced cardiac hypertrophy, we bred miR-155 null mice with α-MHC-calcineurin transgenic mice. As expected, α-MHC-calcineurin transgenic mice underwent dramatic cardiac hypertrophy, with hearts substantially larger than control hearts. However, the hearts of calcineurin/miR-155-knockout mice were much smaller than those of the α-MHC-calcineurin transgenic mice (Figure 3A). The heart weight/body weight ratio was smaller in the calcineurin/miR-155-knockout compound mice than in the α-MHC-calcineurin transgenic mice (Figure 3B). Histological analyses verify the reduction of ventricle wall thickness in calcineurin/miR-155-knockout hearts compared with α-MHC-calcineurin hearts (Figure 3C). Cardiomyocyte hypertrophy, as evidenced by an increase in cross-sectional area in calcineurin transgenic hearts, was drastically reduced in calcineurin/miR-155-knockout hearts (Figure 3D and 3E), suggesting that miR-155 is required for calcineurin transgene–induced cardiomyocyte hypertrophy. We also observed that loss of miR-155 reduced the development of fibrosis, which is induced by the calcineurin transgene and associated with cardiac hypertrophy and remodeling (Figure 3F).
Echocardiography analyses indicated that loss of miR-155 reduced cardiac-specific calcineurin transgene–induced thickening of the LV-free wall (Figure 3G; Online Table III). In addition, the LV end-systolic internal dimension was reduced in calcineurin/miR-155-knockout hearts compared with α-MHC-calcineurin hearts (Online Table III). As a consequence, cardiac function, measured as fractional shortening, was markedly improved in the calcineurin/miR-155-knockout mice compared with α-MHC-calcineurin mice (Figure 3G). Most importantly, loss of miR-155 substantially increased the survival rate of calcineurin transgenic mice (Figure 3H), highlighting the critical role of miR-155 in the regulation of pathological cardiac hypertrophy and heart failure.
Next, we examined the expression of hypertrophic markers brain natriuretic peptide and β-MHC, which was dramatically induced in the hearts of calcineurin transgenic mice. We found that the expression levels of both transcripts and the β-MHC protein were repressed in the hearts of the calcineurin/miR-155-knockout compound mice compared with controls (Figure 3I and 3J). These results indicate that miR-155 participates in the calcineurin-dependent cardiac hypertrophy pathway.
Inhibition of Endogenous MiR-155 Suppresses Cardiomyocyte Hypertrophy in Isolated Cardiomyocytes
The above results, generated from miR-155-knockout mice, strongly suggest that miR-155 plays a vital role in the regulation of cardiac hypertrophy in vivo. However, miR-155 is expressed in multiple cell and tissue types in addition to cardiomyocytes, so the global loss-of-function strategy used above cannot fully rule out the possibility that miR-155 acts in noncardiomyocytes to regulate cardiac hypertrophy. To overcome this limitation and more specifically define the function of miR-155 in cardiomyocytes, we isolated and cultured neonatal cardiomyocytes from wild-type and miR-155-knockout hearts. Isolated cardiomyocytes were treated with phenylephrine to induce hypertrophy. Whereas cardiomyocytes isolated from wild-type control hearts developed massive hypertrophy after phenylephrine treatment, as evidenced by an increase in cell size and organized sarcomere structure, hypertrophic growth was markedly suppressed in miR-155-knockout cardiomyocytes (Figure 4A; high magnification images in Online Figure I). Quantitative measurement of cardiomyocyte size confirmed this observation (Figure 4B). We examined the expression of hypertrophy-induced fetal genes, including atrial natriuretic peptide (ANP) and β-MHC. We found that the expression of these fetal genes was substantially induced by phenylephrine treatment in wild-type control neonatal cardiomyocytes. This phenylephrine-induced increase is suppressed in miR-155-knockout cardiomyocytes (Figure 4C).
To independently verify the above observation, we isolated neonatal cardiomyocytes from rats and transfected them with miR-155 inhibitors, as previously reported.23,24 Cultured cardiomyocytes were then treated with phenylephrine to induce hypertrophy. As expected, inhibition of endogenous miR-155 in cardiomyocytes significantly repressed phenylephrine-induced hypertrophy, suggesting that miR-155 is required for the development of hypertrophy in cardiomyocytes (Figure 4D and 4E; high magnification images in Online Figure II). We examined the cardiac hypertrophy markers atrial natriuretic peptide and β-MHC and found that their expression is induced by phenylephrine treatment in wild-type cardiomyocytes. This phenylephrine-induced expression was reduced in miR-155 inhibitor–treated cardiomyocytes compared with controls (Figure 4F and 4G). Together, these data support the view that miR-155 is required for cardiomyocyte hypertrophy. Furthermore, our results suggest that miR-155 could mediate agonist-induced hypertrophic growth.
Regulation of MiR-155 Target Genes
Individual miRNAs can repress the expression of many targets simultaneously, whereas a protein-coding target transcript can also be repressed by multiple miRNAs at the same time. Many miR-155 target genes have been identified previously, primarily in cancer cells and the immune system.25,26 In a recent study, transcriptome-wide screening for miR-155 targets was performed in activated CD4+ T cells. Using differential high-throughput sequencing of RNA isolated by crosslinking immunoprecipitation to identify miR-155 targets from wild-type and miR-155 null T cells, the investigators identified 191 miR-155 canonical and noncanonical targets.27
We reasoned that many of the miR-155 targets identified in T cells are also expressed in the heart and that their expression should be upregulated in miR-155-knockout hearts. We first compared the 191 miR-155 targets identified from T cells with the list of 257 putative miR-155 targets predicted by the TargetScan algorithm. We identified 35 of them as common, including the Mef2a gene, which we have previously identified (Online Table IV).17 Next, we tested whether the expression of miR-155 targets was increased in the hearts of miR-155-knockout mice. qPCR analyses showed that the expression of several predicted targets was upregulated in miR-155-knockout hearts. These include Jarid2 and MAFb (v-maf musculoaponeurotic fibrosarcoma oncogene family, protein B) (Figure 5A). Jarid2 is a histone demethylase, and previous studies have demonstrated that it plays a central role in cardiac development and hypertrophy.28–30 We, therefore, focused on Jarid2 and examined its expression in hypertrophic hearts in more detail. We found that Jarid2 expression was increased in neonatal cardiomyocytes isolated from miR-155-knockout mice (Figure 5B). We further determined that the expression of this gene was increased in the heart of calcineurin/miR-155-knockout mice compared with that in α-MHC-calcineurin controls (Figure 5C). To confirm further that miR-155 represses the expression of Jarid2 transcripts in cardiomyocytes, neonatal rat cardiomyocytes were transfected with miR-155 inhibitors or control inhibitors, and the expression level of Jarid2 transcripts was determined using qPCR. Jarid2 expression level was increased when endogenous miR-155 was antagonized by miR-155 inhibitors (Figure 5D), suggesting that Jarid2 is a canonical miR-155 target in cardiomyocytes.
We performed luciferase reporter assays to examine the direct repression of Jarid2 by miR-155. We built luciferase reporters containing the 3′ untranslated regions of the mouse Jarid2 gene and tested their repression by miR-155. miR-155 potently repressed the expression of the Jarid2 3′ untranslated region luciferase reporter. An miR-155 sensor reporter was used as a positive control (Figure 5E). When the two miR-155 targeting sites were mutated, miR-155–mediated repression was lost (Figure 5E), demonstrating the specificity of this repression.
Jarid2 Mediates the Function of MiR-155 in Cardiomyocytes
Next, we investigated whether Jarid2 mediates the function of miR-155 in the regulation of cardiomyocyte hypertrophy. We hypothesized that if the function of miR-155 is mediated by Jarid2, which is increased in miR-155-knockout hearts, then inhibition of Jarid2 should, at least in part, rescue the loss-of-miR-155 phenotype in cardiomyocytes. We designed several independent small interfering RNAs to knockdown endogenous Jarid2 in neonatal rat cardiomyocytes (Online Figure III). Neonatal mouse cardiomyocytes were isolated from miR-155-knockout and control hearts. Cultured cardiomyocytes were then treated with phenylephrine to induce hypertrophy. Whereas phenylephrine-induced hypertrophic growth was markedly suppressed in miR-155-knockout cardiomyocytes, as shown by reduced cell size and loss of organized sarcomere structure and consistent with previous observation, Jarid2 knockdown derepresses this loss-of-miR-155 phenotype (Figure 6A; high magnification images in Online Figure IV). Quantification of cardiomyocyte cell size confirms this observation (Figure 6B). Analyses of the expression of hypertrophic marker genes ANP and β-MHC show that inhibition of Jarid2 partially restores the expression of these genes, further supporting the view that Jarid2 mediates miR-155–dependent hypertrophic growth (Figure 6C).
We decided to perform independent experiments to confirm the above observations. We isolated neonatal rat cardiomyocytes and inhibited endogenous miR-155 by specific inhibitors. We found that inhibition of Jarid2 partially rescues hypertrophic growth, which is inhibited by the loss of miR-155 (Figure 6D; high magnification images in Online Figure V), consistent with what we observed in miR-155-knockout mouse cardiomyocytes. Quantification of cardiomyocyte cell size and the expression of hypertrophic marker genes demonstrate that the inhibition of Jarid2 reverses the repression of cardiomyocyte hypertrophy resulting from inhibition of miR-155 (Figure 6E and 6F). Together, these data indicate that the function of miR-155 in cardiomyocyte hypertrophy is partially mediated by its target Jarid2.
Our previous studies showed that miR-155 directly targets MEF2A in skeletal muscle cells.17 Although the mRNA level of Mef2a was not altered in the hearts of miR-155 knockout mice (Figure 5A), we asked whether miR-155 could decrease the MEF2A protein level. As expected, the expression of endogenous MEF2A protein was elevated in the hearts of miR-155 knockout mice (Online Figure VI), suggesting that miR-155 represses MEF2A expression at the translational step.
In this study, we explored the in vivo function of miR-155 in the heart and found that miR-155 plays a critical role in the regulation of cardiomyocyte hypertrophy. We demonstrated that cardiomyocyte hypertrophy, induced by pressure overload or a calcineurin transgene, was attenuated in miR-155-knockout hearts. Genetic deletion of miR-155 prevented progression to dilated cardiomyopathy and heart failure and substantially extended lifespan in calcineurin-transgenic (Tg) mice, indicating that inhibition of miR-155 could become an effective therapeutic approach to prevent or minimize cardiac hypertrophy and heart failure.
Although our current investigation was under preparation, a recent study reported that targeted deletion of miR-155 suppressed cardiac hypertrophy in response to stress. The authors suggested that macrophage-expressed miR-155 is responsible for the induction of cardiac hypertrophy.16 Our studies demonstrate that miR-155 also acts in cardiomyocytes to regulate hypertrophy directly. We provided multiple lines of evidence to support this conclusion. (1) miR-155-knockout/calcineurin-Tg compound mice exhibit decreased cardiac hypertrophy compared with calcineurin-Tg mice. The cardiac hypertrophy exhibited in the calcineurin-Tg heart is directly induced by cardiomyocyte-specific overexpression of calcineurin, driven by the cardiomyocyte-specific α-MHC promoter. Therefore, the observation that loss of miR-155 in miR-155-knockout mice suppresses the calcineurin-Tg hypertrophic phenotype strongly suggests that cardiomyocyte-expressed miR-155 is directly responsible for the development of hypertrophy. (2) Inhibition of endogenous miR-155 represses agonist-induced hypertrophy in isolated neonatal rat cardiomyocytes. (3) Similarly, isolated neonatal mouse cardiomyocytes from miR-155-knockout hearts failed to develop cardiomyocyte hypertrophy in response to phenylephrine stimulation. In the future, it will be necessary to generate cardiomyocyte-specific miR-155 knockout mice to more precisely define the in vivo function of miR-155 in cardiomyocytes. We predict that cardiomyocyte-specific deletion of miR-155 will, at least in part, suppress pathomechanically induced cardiac hypertrophy in vivo. Together, previously published studies and results from the current investigation establish a critical role of miR-155 in cardiac hypertrophy and remodeling. It is evident that miR-155 regulates cardiomyocyte hypertrophy autocrinally via myocyte-expressed miR-155 or paracrinally through macrophage-expressed miR-155.
Among many miR-155 targets, we found that the expression of Jarid2 was significantly increased in the hearts of miR-155-knockout mice. Furthermore, we demonstrated that Jarid2 expression was elevated in isolated cardiomyocytes when endogenous miR-155 was inhibited. Jarid2 was previously shown to be a key transcriptional regulator of cardiac development and function.28,29 Genetic deletion of Jarid2 resulted in embryonic lethality. There was an increase in cardiomyocyte proliferation in Jarid2 null hearts, at least in part because of the derepression of cyclin D expression.29 Jarid2 was previously shown to repress the expression of ANP, a hallmark of cardiac hypertrophy.31,32 In light of its role in ANP repression and inhibition of cardiac hypertrophy, our finding that Jarid2 was substantially increased in the hearts of miR-155-knockout mice under stress strongly suggests that Jarid2 is a key miR-155 target that mediates its function in cardiac hypertrophy and remodeling. Interestingly, although we found that inhibition of endogenous Jarid2 in cardiomyocytes could partially rescue the effect of miR-155 loss, we noticed that inhibition of Jarid2 by itself did not lead to hypertrophy. As a matter of fact, inhibition of Jarid2 slightly reduces phenylephrine-induced hypertrophy in neonatal cardiomyocytes. These observations indicate that Jarid2 may play distinct roles during the development of hypertrophy. Evidently, the identification of additional miR-155 targets in the heart and the determination of how each target mediates the function of miR-155 will remain a challenging task for future investigation. Nevertheless, it is conceivable that the expression and function of miR-155 is associated with human cardiovascular disease and that miR-155 is a putative therapeutic target for cardiac defects.
We thank members of the Wang laboratory for advice and support. We are grateful to Dr John McDermott (York University, Canada) for the generous gift of the anti–myocyte enhancer factor 2A antibody. We thank Fei Fei Wang for careful reading of the article.
Sources of Funding
Work in the Wang laboratory is supported by the March of Dimes Foundation and the National Institutes of Health (NIH; HL085635 and HL116919). M. Kataoka is supported by Banyu Life Science Foundation International. Z.-P. Huang is supported by NIH T32HL007572. D.-Z. Wang is an Established Investigator of the American Heart Association.
In February 2014, the average time from submission to first decision for all original research papers submitted to Circulation Research was 13.8 days.
The online-only Data Supplement is available with this article at http://circres.ahajournals.org/lookup/suppl/doi:10.1161/CIRCRESAHA.114.303784/-/DC1.
- Nonstandard Abbreviations and Acronyms
- left ventricular
- myocyte enhancer factor 2A
- myosin heavy chain
- quantitative polymerase chain reaction
- transverse aortic constriction
- Received February 21, 2014.
- Revision received March 18, 2014.
- Accepted March 21, 2014.
- © 2014 American Heart Association, Inc.
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Novelty and Significance
What Is Known?
The adult heart remodels in response to pathological and physiological conditions.
MicroRNAs are small noncoding RNAs that regulate gene expression and function.
MicroRNA-155 (miR-155) plays a key role in the immune system.
What New Information Does This Article Contribute?
miR-155 is required for the development of cardiac hypertrophy in response to stress.
Inhibition of miR-155 protects cardiac function in a mouse model of cardiac hypertrophy.
miR-155 could be a therapeutic target for the treatment of pathological cardiac hypertrophy.
miR-155 has been implicated in a variety of biological processes and diseases, including immune disorders and cancer. However, the expression and function of this microRNA in the cardiovascular system have not been fully established. In this study, we found that miR-155 plays a key role in regulating cardiac hypertrophy, both in vivo in intact hearts and in vitro in isolated cardiomyocytes. We identified Jarid2 as a direct miR-155 target that mediates its function in cardiomyocytes. These findings suggest that miR-155 may be a potential therapeutic target in the prevention or treatment of cardiac hypertrophy.