MiR-33 promotes myocardial fibrosis by inhibiting MMP16 and stimulating p38 MAPK signaling
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Zhen Chen1,2,3, Hua-Sheng Ding1,2,3, Xin Guo1,2,3, Jing-Jing Shen1,2,3, Di Fan1,2,3, Yan Huang1,2,3 and Cong-Xin Huang1,2,3
1Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan University, Wuhan 430060, PR China
2Institute of Cardiovascular Diseases, Wuhan University, Wuhan 430060, PR China
3Hubei Key Laboratory of Cardiology, Wuhan 430060, PR China
Cong-Xin Huang, email: [email protected]
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
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.
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