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.