Understanding the regulation of cardiomyocyte growth is crucial for the management of adverse ventricular remodeling and heart failure. MicroRNA-378 (miR-378) is a newly described member of the cardiac enriched miRNAs which is expressed only in cardiac myocytes and not in cardiac fibroblasts. We have previously shown that miR-378 regulates cardiac growth during post-natal period by direct targeting of IGF1R (J Biol Chem 287, 12913-12926, 2012). Here, we report that miR-378 is an endogenous negative regulator of cardiac hypertrophy, and its levels are down regulated during hypertrophic growth of the heart and during heart failure. In primary cultures of cardiomyocytes, over expression of miR-378 blocked PE-stimulated Ras-activity and it also prevented activation of two major growth-promoting signaling pathways, PI3K-AKT and Raf1-MEK1-ERK1/2, acting downstream of Ras-signaling. Over expression of miR-378 suppressed PE-induced phosphorylation of S6 ribosomal kinase, pERK1/2, pAKT, pGSK3ß and nuclear accumulation of NFAT. There was also suppression of fetal gene program that was induced by PE. Experiments carried out to delineate the mechanism behind the suppression of Ras, led us to identify Grb2, an upstream component of Ras-signaling, as a bone-fide direct target of miR-378-mediated regulation. Deficiency of miR-378 alone was sufficient to induce fetal gene expression, which was prevented by knocking down of Grb2 expression and by blocking of Ras-activation, thus suggesting that miR-378 interferes with Ras-activation by targeting Grb2. Our study demonstrates that miR-378 is an endogenous negative regulator of Ras-signaling and cardiac hypertrophy and its deficiency contributes to the development of cardiac hypertrophy.

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