Format

Send to

Choose Destination
Proc Natl Acad Sci U S A. 2016 Jun 21;113(25):6949-54. doi: 10.1073/pnas.1603127113. Epub 2016 Jun 6.

IGF-1 degradation by mouse mast cell protease 4 promotes cell death and adverse cardiac remodeling days after a myocardial infarction.

Author information

1
Department of Medicine (Cardiology), Emory University School of Medicine, Atlanta, GA 30322;
2
Department of Surgery (Carlyle Fraser Heart Center), Emory University School of Medicine, Atlanta, GA 30322;
3
Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden; Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, Uppsala, Sweden;
4
Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, Uppsala, Sweden;
5
Victor Chang Cardiac Research Institute, Sydney, NSW 2010, Australia.
6
Department of Medicine (Cardiology), Emory University School of Medicine, Atlanta, GA 30322; ahusai2@emory.edu nnaqvi@emory.edu.

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.

KEYWORDS:

cardioprotection; chymase; insulin-like growth factor-1; ischemia-reperfusion injury; mouse mast cell protease 4

PMID:
27274047
PMCID:
PMC4922143
DOI:
10.1073/pnas.1603127113
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center