ZYZ-168 alleviates cardiac fibrosis after myocardial infarction through inhibition of ERK1/2-dependent ROCK1 activation
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...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
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Nature Publishing Group
2017
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| Online Access: | https://eprints.nottingham.ac.uk/41763/ |
| _version_ | 1848796349129031680 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Luo, Shanshan |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | 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. |
| first_indexed | 2025-11-14T19:46:34Z |
| format | Article |
| id | nottingham-41763 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| last_indexed | 2025-11-14T19:46:34Z |
| publishDate | 2017 |
| publisher | Nature Publishing Group |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-417632020-05-04T18:36:43Z https://eprints.nottingham.ac.uk/41763/ 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 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. Nature Publishing Group 2017-03-07 Article PeerReviewed 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 http://www.nature.com/articles/srep43242 doi:10.1038/srep43242 doi:10.1038/srep43242 |
| spellingShingle | 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 ZYZ-168 alleviates cardiac fibrosis after myocardial infarction through inhibition of ERK1/2-dependent ROCK1 activation |
| title | ZYZ-168 alleviates cardiac fibrosis after myocardial infarction through inhibition of ERK1/2-dependent ROCK1 activation |
| title_full | ZYZ-168 alleviates cardiac fibrosis after myocardial infarction through inhibition of ERK1/2-dependent ROCK1 activation |
| title_fullStr | ZYZ-168 alleviates cardiac fibrosis after myocardial infarction through inhibition of ERK1/2-dependent ROCK1 activation |
| title_full_unstemmed | ZYZ-168 alleviates cardiac fibrosis after myocardial infarction through inhibition of ERK1/2-dependent ROCK1 activation |
| title_short | ZYZ-168 alleviates cardiac fibrosis after myocardial infarction through inhibition of ERK1/2-dependent ROCK1 activation |
| title_sort | zyz-168 alleviates cardiac fibrosis after myocardial infarction through inhibition of erk1/2-dependent rock1 activation |
| url | https://eprints.nottingham.ac.uk/41763/ https://eprints.nottingham.ac.uk/41763/ https://eprints.nottingham.ac.uk/41763/ |