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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; Zhu, Yi Zhun

Authors

Shanshan Luo

Tran Ba Hieu

Fenfen Ma

Ying Yu

Zhonglian Cao

Minjun Wang

Weijun Wu

Yicheng Mao

PETER ROSE Peter.Rose@nottingham.ac.uk
Assistant Professor

Betty Yuen-Kwan Law

Yi Zhun Zhu



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.

Citation

Luo, S., Hieu, T. B., Ma, F., Yu, Y., Cao, Z., Wang, M., …Zhu, Y. Z. (in press). ZYZ-168 alleviates cardiac fibrosis after myocardial infarction through inhibition of ERK1/2-dependent ROCK1 activation. Scientific Reports, 7, Article 43242. https://doi.org/10.1038/srep43242

Journal Article Type Article
Acceptance Date Jan 17, 2017
Online Publication Date Mar 7, 2017
Deposit Date Apr 5, 2017
Publicly Available Date Mar 28, 2024
Journal Scientific Reports
Electronic ISSN 2045-2322
Publisher Nature Publishing Group
Peer Reviewed Peer Reviewed
Volume 7
Article Number 43242
DOI https://doi.org/10.1038/srep43242
Public URL https://nottingham-repository.worktribe.com/output/848852
Publisher URL http://www.nature.com/articles/srep43242

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