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MiR-33 promotes myocardial fibrosis by inhibiting MMP16 and stimulating p38 MAPK signaling

2018; Impact Journals LLC; Volume: 9; Issue: 31 Linguagem: Inglês

10.18632/oncotarget.25173

1949-2553

Zhen Chen, Hua‐Sheng Ding, Xin Guo, Jingjing Shen, Di Fan, Yan Huang, Congxin Huang,

Peptidase Inhibition and Analysis

// Zhen Chen 1, 2, 3 , Hua-Sheng Ding 1, 2, 3 , Xin Guo 1, 2, 3 , Jing-Jing Shen 1, 2, 3 , Di Fan 1, 2, 3 , Yan Huang 1, 2, 3 and Cong-Xin Huang 1, 2, 3 1 Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan University, Wuhan 430060, PR China 2 Institute of Cardiovascular Diseases, Wuhan University, Wuhan 430060, PR China 3 Hubei Key Laboratory of Cardiology, Wuhan 430060, PR China Correspondence to: Cong-Xin Huang, email: huangcongxin@vip.163.com Keywords: myocardial fibrosis; cardiac fibroblasts; miRNA-33; matrix metalloproteinase 16; p38 MAPK signaling pathway Received: July 31, 2017 Accepted: January 20, 2018 Published: April 24, 2018 ABSTRACT Myocardial fibrosis occurs in the late stages of many cardiovascular diseases, and appears to be stimulated by various microRNAs (miRNAs). We previously found that miR-33 may stimulate cardiac remodeling. Here, we examined the involvement of miR-33 in myocardial fibrosis. Proximal left coronary descending artery occlusion was performed in rat, and antagomiR-33a was injected. Primary cardiac fibroblasts were cultured and transfected with miR-33a mimics and inhibitors. miR-33a levels were increased in the rat after surgery, and collagen deposition and heart fibrosis were observed in vivo . Inhibition of miR-33a suppressed fibroblast proliferation, reduced the mRNA and protein levels of collagen-related markers in vitro and in vivo , and rescued the histological damage in vivo . A dual-luciferase reporter system showed that matrix metalloproteinase 16 (MMP16) gene was the direct target of MiR-33a. These results suggest that miR-33 promoted myocardial fibrosis by inhibiting MMP16 and stimulating p38 mitogen-activated protein kinase (p38 MAPK) signaling pathway. MiR-33 may act as a novel therapeutic target for treating myocardial fibrosis.