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

Luo, Shanshan, Hieu, Tran Ba, Ma, Fenfen, Yu, Ying, Cao, Zhonglian, Wang, Minjun, Wu, Weijun, Mao, Yicheng, Rose, Peter, 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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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
RIS ID: https://nottingham-repository.worktribe.com/output/848852
Schools/Departments: University of Nottingham, UK > Faculty of Science > School of Biosciences > Division of Food Sciences
Identification Number: https://doi.org/10.1038/srep43242
Depositing User: Eprints, Support
Date Deposited: 05 Apr 2017 10:24
Last Modified: 04 May 2020 18:36
URI: https://eprints.nottingham.ac.uk/id/eprint/41763

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