title: MicroRNA-503 promotes angiotensin II-induced cardiac fibrosis by targeting Apelin-13.
abstract: Cardiac fibrosis is a major cause of heart failure. MicroRNAs (miRs) are important epigenetic regulators of cardiac function and cardiovascular diseases, including cardiac fibrosis. This study aimed to explore the role of miR-503 and its mechanisms in regulating cardiac fibrosis. miR-503 was found up-regulated in the mouse LV tissues subjected to transverse aortic constriction (TAC) and in neonatal cardiac fibroblasts (CFs) cultured with Angiotension II. The role of miR-503 in regulating CF cell proliferation and/or collagen production in mice neonatal CFs were determined using an MTT assay and RT-PCR respectively. Forced expression of miR-503 increased the cellular proliferation and collagen production in mice neonatal CFs. The effects were abrogated by cotransfection with AMO-503 (a specific inhibitor of miR-503). Injection of antagomiR-503 elevated cardiac function and inhibited the expression of connective tissue growth factor (CTGF) and transforming growth factor (TGF)-β in the TAC mice. Additional analysis revealed that Apelin-13 is a direct target of miR-503, as the overexpression of miR-503 decreased the protein and mRNA expression levels of Apelin-13. In the CFs with pre-treatment of AngII, we transfected AMO-503 into the cells treated with siRNA-APLN. siRNA-APLN abolished the effects of AMO-503 on the production of collagen I and III and the expression of TGF-β and CTGF. Furthermore, pre-treatment of CFs with Apelin-13 (1-100 nmol/l) inhibited angiotensin II-mediated collagen production and activation of CTGF and TGF-β. So we conclude that miR-503 promotes cardiac fibrosis via miR-503-Apelin-13-TGF-β-CTGF-collagen production pathway. Thus, miR-503 is a promising therapeutic target for reducing cardiac fibrosis.
authors.affiliation: Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, China.
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Deng
authors.affiliation: Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, China.
authors.forename: Dandan
authors.initials: D
authors.lastname: Zhao
authors.affiliation: Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, China.
authors.forename: Lanlan
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Yao
authors.affiliation: Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, China.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Guo
authors.affiliation: Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, China.
authors.forename: Lifang
authors.initials: L
authors.lastname: Lv
authors.affiliation: Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Leng
authors.affiliation: Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, Harbin Medical University, Harbin, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.affiliation: Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, China.
authors.forename: Guofen
authors.initials: G
authors.lastname: Qiao
authors.affiliation: Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, China.
authors.forename: Hongli
authors.initials: H
authors.lastname: Shan
mesh_terms: D020413:3' Untranslated Regions; D054392:Adipokines / Q000235:genetics* / Q000378:metabolism; D000804:Angiotensin II; D000818:Animals; D000073861:Apelin; D001483:Base Sequence; D001665:Binding Sites; D049109:Cell Proliferation; D002478:Cells, Cultured; D005347:Fibroblasts / Q000502:physiology; D005355:Fibrosis; D015870:Gene Expression; D006331:Heart Diseases / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000502:physiology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference
chemical_list: D020413:3' Untranslated Regions; D054392:Adipokines; D000073861:Apelin; C402826:Apln protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D035683:MicroRNAs; C556275:Mirn503 microRNA, mouse; D000804:Angiotensin II
keywords: Apelin-13; cardiac fibrosis; miR-503