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Int J Biol Sci 2017; 13(1):22-31. doi:10.7150/ijbs.16298
Let-7a Is an Antihypertrophic Regulator in the Heart via Targeting Calmodulin
1. Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang 150081, P. R. China.
Background: MicroRNAs (miRNAs) have been emerged as important regulator in a multiple of cardiovascular disease, including arrhythmia, cardiac hypertrophy and fibrosis, and myocardial infarction. The aim of this study was to investigate whether miRNA let-7a has antihypertrophic effects in angiotensin II (AngII)-induced cardiac hypertrophy.
Methods: Neonatal rat ventricular myocytes (NRVMs) were exposed to AngII for 36 h as a cellular model of hypertrophy; subcutaneous injection of AngII for 2 weeks was used to establish a mouse model of cardiac hypertrophy in vivo study. Cell surface area (CSA) was measured by immunofluorescence cytochemistry; expression of hypertrophy-related genes ANP, BNP, β-MHC was detected by Real-time PCR; luciferase activity assay was performed to confirm the miRNA's binding site in the calmodulin (CaM) gene; CaM protein was detected by Western blot; the hypertrophy parameters were measured by echocardiographic assessment.
Results: The expression of let-7a was decreased in AngII-induced cardiac hypertrophy in vitro and in vivo. Overexpression of let-7a attenuated AngII-induced increase of cell surface area and repressed the increased mRNA levels of ANP, BNP and β-MHC. Dual-luciferase reporter assay showed that let-7a could bind to the 3'UTR of CaM 1 gene. Let-7a downregulated the expression of CaM protein. In vivo, let-7a produced inhibitory effects on cardiac hypertrophy, including the downregulation of cross-sectional area of cardiomyocytes in mouse heart, the reduction of IVSD and LVPWD, the suppression of hypertrophy marker genes ANP, BNP, β-MHC mRNA level, and the downregulation of CaM protein level.
Conclusions: let-7a possesses a prominent anti-hypertrophic property by targeting CaM genes. The findings provide new insight into molecular mechanism of cardiac hypertrophy.
Keywords: Cardiac hypertrophy, miRNA, let-7a, angiotensin Ⅱ, calmodulin.
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How to cite this article:
Zhou X, Sun F, Luo S, Zhao W, Yang T, Zhang G, Gao M, Lu R, Shu Y, Mu W, Zhuang Y, Ding F, Xu C, Lu Y. Let-7a Is an Antihypertrophic Regulator in the Heart via Targeting Calmodulin. Int J Biol Sci 2017; 13(1):22-31. doi:10.7150/ijbs.16298. Available from http://www.ijbs.com/v13p0022.htm