ZYZ-168 alleviates cardiac fibrosis after myocardial infarction through inhibition of ERK1/2-dependent ROCK1 activation.

Autor: Luo S; 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., Hieu TB; Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China., Ma F; Department of Pharmacy, Shanghai Pudong Hospital, Fudan University, Shanghai, China., Yu Y; Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China.; Department of Cardiology, Xin Hua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China., Cao Z; Instrumental Analysis Center, School of Pharmacy, Fudan University, Shanghai, China., Wang M; 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., Wu W; Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China., Mao Y; Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China., Rose P; School of Biosciences, University of Nottingham, Loughborough, Leics LE12 5RD, UK., Law BY; Pharmacy and State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China., Zhu YZ; 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.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2017 Mar 07; Vol. 7, pp. 43242. Date of Electronic Publication: 2017 Mar 07.
DOI: 10.1038/srep43242
Abstrakt: 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.
Databáze: MEDLINE
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