title: Let-7a Is an Antihypertrophic Regulator in the Heart via Targeting Calmodulin.
abstract: 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.
authors.affiliation: 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.; Department of Cardiology (Key Laboratory of Myocardial Ischemia, Ministry of Education), The 2nd Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150081, P. R. China.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhou
authors.affiliation: 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.; Northern Translational Medicine Research and Cooperation Center, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin, Heilongjiang 150081, P. R. China.
authors.forename: Fei
authors.initials: F
authors.lastname: Sun
authors.affiliation: 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.
authors.forename: Shenjian
authors.initials: S
authors.lastname: Luo
authors.affiliation: 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.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.affiliation: 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.
authors.forename: Ti
authors.initials: T
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: Guiye
authors.initials: G
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Ming
authors.initials: M
authors.lastname: Gao
authors.affiliation: 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.
authors.forename: Renzhong
authors.initials: R
authors.lastname: Lu
authors.affiliation: 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.
authors.forename: You
authors.initials: Y
authors.lastname: Shu
authors.affiliation: 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.
authors.forename: Wei
authors.initials: W
authors.lastname: Mu
authors.affiliation: 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.
authors.forename: Yanan
authors.initials: Y
authors.lastname: Zhuang
authors.affiliation: 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.
authors.forename: Fengzhi
authors.initials: F
authors.lastname: Ding
authors.affiliation: 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.
authors.forename: Chaoqian
authors.initials: C
authors.lastname: Xu
authors.affiliation: 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.; Northern Translational Medicine Research and Cooperation Center, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin, Heilongjiang 150081, P. R. China.
authors.forename: Yanjie
authors.initials: Y
authors.lastname: Lu
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics; D002147:Calmodulin / Q000235:genetics / Q000378:metabolism*; D006332:Cardiomegaly / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism*; D002478:Cells, Cultured; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism*; D020097:Natriuretic Peptide, Brain / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D020413:3' Untranslated Regions; D002147:Calmodulin; D035683:MicroRNAs; D012333:RNA, Messenger; D000804:Angiotensin II; D020097:Natriuretic Peptide, Brain; D009320:Atrial Natriuretic Factor
keywords: Cardiac hypertrophy; angiotensin Ⅱ; calmodulin.; let-7a; miRNA