Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 113, Issue 25, Pages 6949-6954Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1603127113
Keywords
insulin-like growth factor-1; chymase; mouse mast cell protease 4; ischemia-reperfusion injury; cardioprotection
Categories
Funding
- Department of Medicine, Emory University
- Carlyle Fraser Heart Center, Emory University Hospital Midtown grant
- NIH [HL079040, HL127726, HL098481, T32HL007745, HL092141, HL093579, HL094373, HL113452]
- American Heart Association [13SDG16460006]
- Swedish Research Council
- Foundation Leducq
- National Health and Medical Research Council of Australia [573732]
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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 post-ischemic heart disease.
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