Tejada, Thor and Tan, Lin and Torres, Rebecca A and Calvert, John W and Lambert, Jonathan P and Zaidi, Madiha and Husain, Murtaza and Berce, Maria D and Naib, Hussain and Pejler, Gunnar and Abrink, Magnus and Graham, Robert M and Lefer, David J and Naqvi, Nawazish and Husain, Ahsan (2016) IGF-1 degradation by mouse mast cell protease 4 promotes cell death and adverse cardiac remodeling days after a myocardial infarction. Proceedings of the National Academy of Sciences of the United States of America (PNAS), 113 (25). pp.6949-6954. ISSN 1091-6490 (OA)
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Abstract
Heart disease is a leading cause of death in adults. Here, we show that a few days after coronary artery ligation and reperfusion, the ischemia-injured heart elaborates the cardioprotective polypeptide, insulin-like growth factor-1 (IGF-1), which activates IGF-1 receptor prosurvival signaling and improves cardiac left ventricular systolic function. However, this signaling is antagonized by the chymase, mouse mast cell protease 4 (MMCP-4), which degrades IGF-1. We found that deletion of the gene encoding MMCP-4 (Mcpt4), markedly reduced late, but not early, infarct size by suppressing IGF-1 degradation and, consequently, diminished cardiac dysfunction and adverse structural remodeling. Our findings represent the first demonstration to our knowledge of tissue IGF-1 regulation through proteolytic degradation and suggest that chymase inhibition may be a viable therapeutic approach to enhance late cardioprotection in postischemic heart disease.
| Item Type: | Article |
|---|---|
| Subjects: | R Medicine > R Medicine (General) |
| Depositing User: | Repository Administrator |
| Date Deposited: | 13 Jun 2016 23:38 |
| Last Modified: | 04 Jan 2017 00:50 |
| URI: | https://eprints.victorchang.edu.au/id/eprint/443 |
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