IGF-1 degradation by mouse mast cell protease 4 promotes cell death and adverse cardiac remodeling days after a myocardial infarction
2016 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 113, no 25, 6949-6954 p.Article in journal (Refereed) PublishedText
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.
Place, publisher, year, edition, pages
2016. Vol. 113, no 25, 6949-6954 p.
insulin-like growth factor-1, chymase, mouse mast cell protease 4, ischemia-reperfusion injury, cardioprotection
Cardiac and Cardiovascular Systems
IdentifiersURN: urn:nbn:se:uu:diva-299564DOI: 10.1073/pnas.1603127113ISI: 000378272400049PubMedID: 27274047OAI: oai:DiVA.org:uu-299564DiVA: diva2:949747
FunderNIH (National Institute of Health), HL079040 HL127726 HL098481 T32HL007745 HL092141 HL093579 HL094373 HL113452Swedish Research Council