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

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 post-ischemic heart disease.

Keywords

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

Published in

Proceedings of the National Academy of Sciences
2016, volume: 113, number: 25, pages: 6949-6954
Publisher: NATL ACAD SCIENCES

SLU Authors

• Pejler, Gunnar

  • Department of Animal Biosciences, Swedish University of Agricultural Sciences
    
  • Uppsala University

• Åbrink, Magnus

  • Department of Animal Biosciences, Swedish University of Agricultural Sciences
    

Associated SLU-program

Future Animal Health and Welfare (until Jan 2017)

UKÄ Subject classification

Immunology in the medical area

Publication identifier

• DOI: https://doi.org/10.1073/pnas.1603127113

Permanent link to this page (URI)

https://res.slu.se/id/publ/79422