Muscle ring finger protein-1 inhibits PKCε activation and prevents cardiomyocyte hypertrophy

Cardiac hypertrophy is accompanied by maladaptive cardiac remodeling, which leads to heart failure or sudden death. MicroRNAs (miRNAs) are a class of small, noncoding RNAs that mediate posttranscriptional gene silencing. Recent studies show that miRNAs are involved in the pathogenesis of hypertrophy, but their signaling regulations remain to be understood. Here, we report that miR-23a is a pro-hypertrophic miRNA, and its expression is regulated by the transcription factor, nuclear factor of activated T cells (NFATc3). The results showed that miR-23a expression was up-regulated upon treatment with the hypertrophic stimuli including isoproterenol and aldosterone. Knockdown of miR-23a could attenuate hypertrophy, suggesting that miR-23a is able to convey the hypertrophic signal. In exploring the molecular mechanism by which miR-23a is up-regulated, we identified that NFATc3 could directly activate miR-23a expression through the transcriptional machinery. The muscle specific ring finger protein 1, an anti-hypertrophic protein, was identified to be a target of miR-23a. Its translation could be suppressed by miR-23a. Our data provide a model in which the miRNA expression is regulated by the hypertrophic transcriptional factor.ardiac hypertrophy is an early milestone of many heart diseases (1, 2), which is associated with changes in gene expression (3). MicroRNAs (miRNAs) are small noncoding RNA molecules that regulate pathophysiological processes such as cell differentiation, apoptosis, cell proliferation, and organ development (4, 5). Recently, the work on miRNAs renovates our understanding about the regulation of cardiac hypertrophy (6, 7). Functional studies reveal that different miRNAs have distinct effects on cardiac hypertrophy. For example, inhibition of miR-133 causes significant cardiac hypertrophy (8). In contrast, miR-208 is required for cardiomyocyte hypertrophy in response to stress and hypothyroidism (9). Overexpression of miR-195 in mice hearts results in severe cardiac hypertrophy (10). Overexpression of miR-214, miR-24, or miR-23a in the cardiomyocytes also causes significant hypertrophy (10). Thus, it appears that miRNAs play multiple and essential roles in the regulation of cardiac hypertrophy.The levels of many miRNAs have been demonstrated to be altered in cardiac hypertrophy by a series of high-throughput miRNA microarray analysis (10-12). Nevertheless, the signaling pathways that regulate the expression of miRNAs during cardiac hypertrophy remain largely unknown. It is reported that serum response factor (SRF) can directly bind to the promoter of miR-1-1 and miR-1-2 genes and activate their expression (13). Nuclear factor of activated T cells (NFAT) is a transcription factor. Currently, 5 isoforms of NFAT have been identified (14) of which NFATc3 is well-documented to play a key role in mediating the hypertrophic signal of calcineurin as well as other stimuli (15). It is not yet clear whether NFATc3 can regulate cardiac hypertrophy through targeting miRNAs.The muscle specific ring finger protein...

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“…Enforced expression of MuRF1 alone does not significantly induce cardiomyocyte atrophy (35). Our present study obtained a similar result.…”

Section: Mir-23a Is Necessary For the Induction Of Hypertrophy Insupporting

confidence: 80%

“…MuRF1 is a crucial anti-hypertrophic factor (16,29,35). It appears that different miRNAs have distinct mechanisms in regulating hypertrophy.…”

Section: Mir-23a Is Necessary For the Induction Of Hypertrophy Inmentioning

confidence: 99%

miR-23a functions downstream of NFATc3 to regulate cardiac hypertrophy

Lin

Murtaza

Wang

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

327

279

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“…MuRF1 mediates degradation of troponin I and, when overexpressed, reduces cardiomyocyte contractility (13). MuRF1 has also been reported to prevent cardiomyocyte hypertrophy in response to protein kinase C activation (18).…”

Section: Discussionmentioning

confidence: 99%

Loss of muscle-specific RING-finger 3 predisposes the heart to cardiac rupture after myocardial infarction

Fielitz¹,

Rooij²,

Spencer³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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RING-finger proteins commonly function as ubiquitin ligases that mediate protein degradation by the ubiquitin-proteasome pathway. Muscle-specific RING-finger (MuRF) proteins are striated muscle-restricted components of the sarcomere that are thought to possess ubiquitin ligase activity. We show that mice lacking MuRF3 display normal cardiac function but are prone to cardiac rupture after acute myocardial infarction. Cardiac rupture is preceded by left ventricular dilation and a severe decrease in cardiac contractility accompanied by myocyte degeneration. Yeast two-hybrid assays revealed four-and-a-half LIM domain (FHL2) and ␥-filamin proteins as MuRF3 interaction partners, and biochemical analyses showed these proteins to be targets for degradation by MuRF3. Accordingly, FHL2 and ␥-filamin accumulated to abnormal levels in the hearts of mice lacking MuRF3. These findings reveal an important role of MuRF3 in maintaining cardiac integrity and function after acute myocardial infarction and suggest that turnover of FHL2 and ␥-filamin contributes to this cardioprotective function of MuRF3.heart failure ͉ cardiac stress response ͉ protein degradation ͉ sarcomere

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“…Activation of E3 ligases CHIP and MDM2 protected myocardium from IR injury (33,34), while activation of Atrogin1 and MuRF1 attenuated cardiac hypertrophy by interacting with calcineurin and PKC⑀, respectively (35,36). The current study adds c-Cbl to the list of E3 ubiquitin ligases that play a role in myocyte protection in response to neutrophil-derived serine proteases.…”

Section: Discussionmentioning

confidence: 99%

c-Cbl Ubiquitin Ligase Regulates Focal Adhesion Protein Turnover and Myofibril Degeneration Induced by Neutrophil Protease Cathepsin G

Rafiq¹,

Guo

Vlasenko

et al. 2012

Journal of Biological Chemistry

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Background:The neutrophil protease cathepsin G induces myocyte anoikis. Results: Cathepsin G promotes c-Cbl activation and interaction with focal adhesion proteins that leads to focal adhesion and myofibril protein degradation and myocyte anoikis. Conclusion: c-Cbl is a key ligase required during cathepsin G-induced focal adhesion and myofibrillar protein degradation. Significance: This is a novel mechanism to regulate focal adhesion and myofibril stability and turnover.

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Muscle ring finger protein-1 inhibits PKCε activation and prevents cardiomyocyte hypertrophy

Cited by 105 publications

References 82 publications

miR-23a functions downstream of NFATc3 to regulate cardiac hypertrophy

miR-23a functions downstream of NFATc3 to regulate cardiac hypertrophy

Loss of muscle-specific RING-finger 3 predisposes the heart to cardiac rupture after myocardial infarction

c-Cbl Ubiquitin Ligase Regulates Focal Adhesion Protein Turnover and Myofibril Degeneration Induced by Neutrophil Protease Cathepsin G

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