Abstract P229: Chymase-mediated Igf-1 Degradation Promotes Delayed Cell Death in Post-ischemic Hearts

Abstract

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 is antagonized by the chymase, mouse mast cell protease-4 (MMCP-4), which degrades IGF-1 (Fig. 1). We found that MMCP-4 deficiency, resulted in sustained IGF-1 levels and IGF-1 receptor prosurvival signaling post-I/R. MMCP-4 deficiency markedly reduced late, but not early, infarct size (~50% reduction: n=5-7, p value= 0.001) by suppressing IGF-1 degradation and, consequently, improving cardiac function (EF: 26% greater, n=21, p value= 0.001) and adverse structural remodeling (Fig. 2). Our findings represent the first demonstration 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.