期刊
SCIENTIFIC REPORTS
卷 7, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/srep43242
关键词
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资金
- National Natural Science Foundation of China [781330080, 81173054]
- Shanghai Committee of Science and Technology of China [14JC1401100]
- Key Laboratory Program of the Education Commission of Shanghai Municipality [ZDSYS14005]
- National Major Scientific and Technological Special Project [2012ZX09103101-064]
- Faculty Research Grants of Macao University of Science and Technology [FRG-17-006-SP]
- National Science and Technology Major Project [2012ZX09501001-001-003]
- National Natural Science Foundation of China [781330080, 81173054]
- Shanghai Committee of Science and Technology of China [14JC1401100]
- Key Laboratory Program of the Education Commission of Shanghai Municipality [ZDSYS14005]
- National Major Scientific and Technological Special Project [2012ZX09103101-064]
- Faculty Research Grants of Macao University of Science and Technology [FRG-17-006-SP]
- National Science and Technology Major Project [2012ZX09501001-001-003]
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 a-smooth muscle actin (a-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-beta 1, phenotypic switches of cardiac fibroblasts to myofibroblasts were observed. Inhibition of ERK1/2 phosphorylation or knockdown of ROCK1 expectedly reduced TGF-beta 1 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.
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