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

Luo, Shanshan and Hieu, Tran Ba and Ma, Fenfen and Yu, Ying and Cao, Zhonglian and Wang, Minjun and Wu, Weijun and Mao, Yicheng and Rose, Peter and Law, Betty Yuen-Kwan and Zhu, Yi Zhun (2017) ZYZ-168 alleviates cardiac fibrosis after myocardial infarction through inhibition of ERK1/2-dependent ROCK1 activation. Scientific Reports, 7 . 43242/1-43242/14. ISSN 2045-2322

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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.

Item Type: Article
Schools/Departments: University of Nottingham, UK > Faculty of Science > School of Biosciences > Division of Food Sciences
Identification Number: 10.1038/srep43242
Depositing User: Eprints, Support
Date Deposited: 05 Apr 2017 10:24
Last Modified: 07 Apr 2017 16:05
URI: http://eprints.nottingham.ac.uk/id/eprint/41763

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