title: ZYZ-168 alleviates cardiac fibrosis after myocardial infarction through inhibition of ERK1/2-dependent ROCK1 activation.
abstract: Selective treatments for myocardial infarction (MI) induced cardiac fibrosis are lacking. In this study, we focus on the therapeutic potential of a synthetic cardio-protective agent named ZYZ-168 towards MI-induced cardiac fibrosis and try to reveal the underlying mechanism. ZYZ-168 was administered to rats with coronary artery ligation over a period of six weeks. Ecocardiography and Masson staining showed that ZYZ-168 substantially improved cardiac function and reduced interstitial fibrosis. The expression of α-smooth muscle actin (α-SMA) and Collagen I were reduced as was the activity of matrix metalloproteinase 9 (MMP-9). These were related with decreased phosphorylation of ERK1/2 and expression of Rho-associated coiled-coil containing protein kinase 1 (ROCK1). In cardiac fibroblasts stimulated with TGF-β1, phenotypic switches of cardiac fibroblasts to myofibroblasts were observed. Inhibition of ERK1/2 phosphorylation or knockdown of ROCK1 expectedly reduced TGF-β1 induced fibrotic responses. ZYZ-168 appeared to inhibit the fibrotic responses in a concentration dependent manner, in part via a decrease in ROCK 1 expression through inhibition of the phosphorylation status of ERK1/2. For inhibition of ERK1/2 phosphorylation with a specific inhibitor reduced the activation of ROCK1. Considering its anti-apoptosis activity in MI, ZYZ-168 may be a potential drug candidate for treatment of MI-induced cardiac fibrosis.
authors.affiliation: Pharmacy and State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China.|Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Luo
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China.
authors.forename: Tran Ba
authors.initials: TB
authors.lastname: Hieu
authors.affiliation: Department of Pharmacy, Shanghai Pudong Hospital, Fudan University, Shanghai, China.
authors.forename: Fenfen
authors.initials: F
authors.lastname: Ma
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China.|Department of Cardiology, Xin Hua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Instrumental Analysis Center, School of Pharmacy, Fudan University, Shanghai, China.
authors.forename: Zhonglian
authors.initials: Z
authors.lastname: Cao
authors.affiliation: Pharmacy and State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China.|Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China.
authors.forename: Minjun
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China.
authors.forename: Weijun
authors.initials: W
authors.lastname: Wu
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China.
authors.forename: Yicheng
authors.initials: Y
authors.lastname: Mao
authors.affiliation: School of Biosciences, University of Nottingham, Loughborough, Leics LE12 5RD, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Rose
authors.affiliation: Pharmacy and State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China.
authors.forename: Betty Yuen-Kwan
authors.initials: BY
authors.lastname: Law
authors.affiliation: Pharmacy and State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China.|Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China.
authors.forename: Yi Zhun
authors.initials: YZ
authors.lastname: Zhu
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000008:administration & dosage*; D004195:Disease Models, Animal; D005355:Fibrosis / Q000473:pathology / Q000517:prevention & control*; D020935:MAP Kinase Signaling System; D009203:Myocardial Infarction / Q000150:complications*; D009206:Myocardium / Q000473:pathology; D051381:Rats; D016896:Treatment Outcome; D054460:rho-Associated Kinases / Q000378:metabolism*
chemical_list: D002316:Cardiotonic Agents; C578418:ROCK1 protein, rat; D054460:rho-Associated Kinases