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ZAK induces MMP-2 activity via JNK/p38 signals and reduces MMP-9 activity by increasing TIMP-1/2 expression in H9c2 cardiomyoblast cells |
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| Authors: | Yi-Chang Cheng Wei-Wen Kuo Hsi-Chin Wu Tung-Yuan Lai Chun-Hsien Wu Jin-Ming Hwang Wen-Hong Wang Fuu-Jen Tsai Jaw-Ji Yang Chih-Yang Huang Chun-Hsien Chu |
| Affiliation: | 1. Emergency Department, China Medical University Hospital, Taichung, Taiwan 2. Department of Biological Science and Technology, China Medical University, Taichung, 404, Taiwan 3. School of Medicine, China Medical University Hospital, Taichung, Taiwan 4. Post-Baccalaureate School of Chinese Medicine, China Medical University, Taichung, 404, Taiwan 5. School of Applied Chemistry, Chung-Shan Medical University, Taichung, Taiwan 6. Department of Nutrition, Taichung Veterans General Hospital, Taichung, Taiwan 7. Department of Pediatrics, Medical Research and Medical Genetics, China Medical University, Taichung, Taiwan 8. School of Dentistry, Chung-Shan Medical University, Taichung, Taiwan 10. Graduate Institute of Basic Medical Science, China Medical University, No. 91, Hsueh-Shih Road, Taichung, 404, Taiwan 11. Department of Health and Nutrition Biotechnology, Asia University, Taichung, 413, Taiwan 9. Graduate Institute of Chinese Medical Science, China Medical University, Taichung, Taiwan |
| Abstract: | Leucine-zipper and sterile-alpha motif kinase (ZAK) is the key intra-cellular mediator protein in cardiomyocyte hypertrophy induction by transforming growth factor beta 1 (TGF-β1) which has also been identified as a profibrotic cytokine involved in cardiac fibrosis progression. We hypothesized whether ZAK over-expression causes cardiac scar formation due to the extra-cellular matrix (ECM) degraded enzyme regulation in this paper. Using immuno-histochemical analysis of the human cardiovascular tissue array, we found a positively significant association between ZAK over-expression and myocardial scars. ZAK over-expression in H9c2 cardiomyoblast cells increases the metalloproteinase tissue inhibitor 1/2 (TIMP-1/2) protein level, which reduces matria metalloproteinase-9 (MMP-9) activity and also activates c-JNK N-terminal kinase 1/2 (JNK1/2) and p38 signaling, which induces MMP-2, possibly resulting in cardiac fibrosis. Taken together, ZAK activity inhibition may be a good strategy to prevent the cardiac fibrosis progression. |
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