IGF-1 degradation by mouse mast cell protease 4 promotes cell death and adverse cardiac remodeling days after a myocardial infarction.
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.
Department of Medicine (Cardiology), Emory University School of Medicine, Atlanta, GA 30322;
Thor
T
Tejada
Department of Medicine (Cardiology), Emory University School of Medicine, Atlanta, GA 30322;
Lin
L
Tan
Department of Medicine (Cardiology), Emory University School of Medicine, Atlanta, GA 30322;
Rebecca A
RA
Torres
Department of Surgery (Carlyle Fraser Heart Center), Emory University School of Medicine, Atlanta, GA 30322;
John W
JW
Calvert
Department of Surgery (Carlyle Fraser Heart Center), Emory University School of Medicine, Atlanta, GA 30322;
Jonathan P
JP
Lambert
Department of Medicine (Cardiology), Emory University School of Medicine, Atlanta, GA 30322;
Madiha
M
Zaidi
Department of Medicine (Cardiology), Emory University School of Medicine, Atlanta, GA 30322;
Murtaza
M
Husain
Department of Medicine (Cardiology), Emory University School of Medicine, Atlanta, GA 30322;
Maria D
MD
Berce
Department of Medicine (Cardiology), Emory University School of Medicine, Atlanta, GA 30322;
Hussain
H
Naib
Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden; Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, Uppsala, Sweden;
Gunnar
G
Pejler
Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, Uppsala, Sweden;
Magnus
M
Abrink
Victor Chang Cardiac Research Institute, Sydney, NSW 2010, Australia.
Robert M
RM
Graham
Department of Surgery (Carlyle Fraser Heart Center), Emory University School of Medicine, Atlanta, GA 30322;
David J
DJ
Lefer
Department of Medicine (Cardiology), Emory University School of Medicine, Atlanta, GA 30322; ahusai2@emory.edu nnaqvi@emory.edu.
Nawazish
N
Naqvi
Department of Medicine (Cardiology), Emory University School of Medicine, Atlanta, GA 30322; ahusai2@emory.edu nnaqvi@emory.edu.
Ahsan
A
Husain
D000818:Animals; D016923:Cell Death; D006868:Hydrolysis; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D051379:Mice; D009203:Myocardial Infarction / Q000503:physiopathology*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*
D007334:Insulin-Like Growth Factor I; D012697:Serine Endopeptidases; C066932:mast cell protease 4
cardioprotection; chymase; insulin-like growth factor-1; ischemia-reperfusion injury; mouse mast cell protease 4