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IGF-1 degradation by mouse mast cell protease 4 promotes cell death and adverse cardiac remodeling days after a myocardial infarction
Emory Univ, Sch Med, Dept Med Cardiol, Atlanta, GA 30322 USA..
Emory Univ, Sch Med, Dept Med Cardiol, Atlanta, GA 30322 USA..
Emory Univ, Sch Med, Dept Med Cardiol, Atlanta, GA 30322 USA..
Emory Univ, Sch Med, Dept Surg, Carlyle Fraser Heart Ctr, Atlanta, GA 30322 USA..
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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
Abstract [en]

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.
Keyword [en]
insulin-like growth factor-1, chymase, mouse mast cell protease 4, ischemia-reperfusion injury, cardioprotection
National Category
Cardiac and Cardiovascular Systems
Identifiers
URN: urn:nbn:se:uu:diva-299564DOI: 10.1073/pnas.1603127113ISI: 000378272400049PubMedID: 27274047OAI: oai:DiVA.org:uu-299564DiVA: diva2:949747
Funder
NIH (National Institute of Health), HL079040 HL127726 HL098481 T32HL007745 HL092141 HL093579 HL094373 HL113452Swedish Research Council
Available from: 2016-07-22 Created: 2016-07-22 Last updated: 2016-07-22Bibliographically approved

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Pejler, Gunnar
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Department of Medical Biochemistry and Microbiology
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