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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Reactive oxygen species and doxorubicin could induce mitochondrial fission and apoptosis in cardiomyocytes. Concomitantly, mitofusin 1 (Mfn1) was downregulated, whereas miRNA 140 (miR-140) was upregulated upon apoptotic stimulation. We investigated whether Mfn1 and miR-140 play a functional role in mitochondrial fission and apoptosis. Ectopic expression of Mfn1 attenuated mitochondrial fission and apoptosis. Knockdown of miR-140 inhibited mitochondrial fission. Our results further revealed that knockdown of miR-140 was able to reduce myocardial infarct sizes in an animal model. We observed that miR-140 could suppress the expression of Mfn1, and it exerted its effect on mitochondrial fission and apoptosis through targeting Mfn1. Our data revealed that mitochondrial fission occurs in cardiomyocytes and can be counteracted by Mfn1. However, the function of Mfn1 is negatively regulated by miR-140. Our present work suggests that Mfn1 and miR-140 are integrated into the program of cardiomyocyte apoptosis.