Shanshan Luo
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
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 | Apr 5, 2017 |
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 |
Contract Date | Apr 5, 2017 |
Files
Zhu 2017 srep43242.pdf
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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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