Talk on Saturday 12:20-12:40pm submitted by Peng Yao
miR-574-5p Plays a Cardioprotective Role in Heart Failure
Jiangbin Wu (Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA), Ricky Chan (Computational Biology Core, Institute for Computational Biology, Case Western Reserve University, Cleveland, OH, USA), Peng Yao (Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA)
Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide. One major etiology of CVD is dysregulation of cardiac gene expression by transcription factors (TFs), microRNAs (miRNAs) and RNA-binding proteins (RBPs). Cardiac hypertrophy and heart failure (HF) are accompanied by changes in the expression of specific miRNAs in pathological cardiac remodelling1. miRNAs are small non-coding RNAs involved in gene expression regulation via miRNA-induced silencing complex (miRISC)2,3. TFs are usually poor small-molecule drug targets. However, miRNAs can act as unique therapeutic agents because they can target multiple TFs in the same pathological pathway. Here, we investigated the function and molecular mechanisms of miR-574-5p in cardiac hypertrophy and HF. We showed that miR-574-5p was enriched in murine HF tissues versus normal hearts. In vitro, transfection of miR-574-5p mimics in mouse cardiomyocytes (CM) protected the cells from isoproterenol (ISO, a β-adrenergic agonist)-induced hypertrophy and hypoxia-serum starvation-induced cell death. In vivo, miR-574 knockout (KO) mice exhibited an advanced cardiac hypertrophy phenotype associated with increased fibrosis and enlarged CM, compared to wild-type (WT) C57BL/6 mice after subcutaneous ISO injection and transverse aortic constriction (TAC) surgery. miRACE analysis indicated that miR-574-5p repressed mRNA translation of three pro-hypertrophic Mef2 TFs: Mef2a, Mef2c and Mef2d. Protein expression of Mef2 TFs and mRNA transcription of their downstream hypertrophic and fibrotic marker genes was significantly induced in miR-574 KO mice compared to WT mice under hypertrophic stress. In parallel, RNA-Seq analysis revealed that a pro-apoptotic RBP Mex3d was a major target down-regulated at the level of mRNA stability. Together, these findings uncover miR-574-5p as a novel cardioprotective miRNA that regulates cardiac gene expression and modulates pathological cardiac hypertrophy and remodelling in CM.
1. van Rooij, E., et al. 2006. A signature pattern of stress-responsive microRNAs that can evoke cardiac hypertrophy and heart failure. Proceedings of the National Academy of Sciences of the United States of America 103:18255-18260.
2. Bartel, D.P. 2009. MicroRNAs: target recognition and regulatory functions. Cell 136:215-233.
3. Yao, P., Eswarappa, S.M. & Fox, P.L. 2015. Translational control mechanisms in angiogenesis and vascular biology. Current atherosclerosis reports 17:506.
Keywords: miRNA, RNA-binding protein, cardiac disease