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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

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.

Journal Article Type Article
Journal Scientific Reports
Print ISSN 2045-2322
Electronic ISSN 2045-2322
Publisher Nature Publishing Group
Peer Reviewed Peer Reviewed
Volume 7
Article Number 43242
APA6 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, https://doi.org/10.1038/srep43242
DOI https://doi.org/10.1038/srep43242
Publisher URL http://www.nature.com/articles/srep43242
Copyright Statement Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0





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