Abstract
Myocardin (MYOCD), a cardiac specific transcriptional co-activator is up-regulated in heart failure (HF). Up-regulation of MYOCD expression has been proposed to be an important adaptive response in cardiac remodelling. However, molecular mechanisms contributing to increased cardiac MYOCD expression in HF are not known. The goal of this study was to identify microRNA(s) regulating cardiac MYOCD expression and to study the effect of cardiac modulation of MYOCD specific miRNA in an animal model of HF. miRNA(s) targeting MYOCD were identified using in silico approach and validated by 3’-UTR luciferase reporter assay. Cardiac expression of miRNA was measured in endomyocardial biopsies from idiopathic DCM (IDCM) patients, renal artery ligation rat model of HF (RAL) and in Ang II treated cardiomyocytes by real-time PCR. miRNA-33a, miRNA-33b, miRNA-139 and miRNA-542 were identified with MYOCD as putative target. Cardiac expression of miRNA-33a and miRNA-33b was significantly decreased, whereas expression of miRNA-139 and miRNA-542 was not altered in IDCM. miRNA-33a expression was also decreased in RAL and in Ang II treated cardiomyocytes. Luciferase assay confirmed MYOCD as target gene for miRNA-33a. miRNA-33a overexpression significantly decreased expression of MYOCD, ANP and fibrotic genes in Ang II treated cardiomyocytes. Cardiac specific delivery of miRNA-33a, using a homing peptide conjugated siRNA, attenuated cardiac hypertrophy and fibrosis, decreased expression of ANP, β-MHC and fibrotic genes and ameliorated the impaired diastolic dysfunction in RAL. Our results provide the first evidence that miRNA-33a regulates MYOCD expression and cardiac specific augmentation of miRNA-33a attenuated cardiac remodelling and partially restored left ventricular function. Our results suggest miR-33a as a potential therapeutic target in reversal of cardiac remodelling and improvement in heart function in HF.
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