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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

Significance Coronary heart disease is a leading cause of death worldwide. After acute myocardial infarction, early reperfusion limits infarct progression and improves clinical outcomes. However, despite reperfusion, the incidence of heart failure and cardiovascular deaths remains unacceptably high. Here, we report that a few days after ischemia, the reperfused heart transiently elaborates the cardioprotective polypeptide, insulin-like growth factor-1 (IGF-1). However, tissue IGF-1 levels increase only transiently because it is rapidly degraded by the chymase, mouse mast cell protease 4. Mouse mast cell protease 4 deletion promotes cardiac cell survival by reducing IGF-1 degradation, which ameliorates cardiac dysfunction caused by ischemic injury. Our findings suggest that chymase inhibition may be a viable therapeutic approach to enhance late cardioprotection in postischemic heart disease. 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.