IGF-1 degradation by mouse mast cell protease 4 promotes cell death and adverse cardiac remodeling days after a myocardial infarction

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 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.insulin-like growth factor-1 | chymase | mouse mast cell protease 4 | ischemia-reperfusion injury | cardioprotection

Mast cell chymase protects against acute ischemic kidney injury by limiting neutrophil hyperactivation and recruitment

“…Locally, we found an increase of MCPT4 in kidney capsule extracts, while FcεRIb expressing MCs remain stable. Likely, kidney capsule MCs synthesize new chymase following local degranulation after renal IRI, as already reported after heart infarction, 52 may also enter local inflammatory sites from systemic sources.…”

“…This protective function may be operative only during the acute phase, as MCPT4 also has detrimental effects in IRI during the later remodeling phase, as has been found in ischemic heart disease. 52 In fact, previous analyses of MCs and their mediators in kidney disease have revealed a complex picture. Some studies on MCs and MCPT4 showed that they aggravate glomerulonephritis, 26,53 whereas others reported diseaseprotective effects.…”

“…79 MCPT4 may also have different actions in the long term, as evidenced in ischemic heart disease. 52 Likewise, blocking only 1 effector arm, i.e., blocking CD162, may not be sufficient. General regulators such as chymase may represent an important new avenue to prevent excessive neutrophil infiltration, thereby favoring their beneficial over pathologic roles.…”

Highly Selective Cleavage of Cytokines and Chemokines by the Human Mast Cell Chymase and Neutrophil Cathepsin G

“…In contrast, fibronectin and angiotensin I seem to be common targets for the chymases of many mammals (37). Recently, it also was shown that mMCP-4 degrades IGF-1, leading to adverse effects in cardiac remodeling after infarction (25). In this study, we showed that HC and hCG cleave human IGF-1 (Fig.…”

“…Following our analysis of the above 50 cytokines and chemokines, an article was published showing the cleavage of insulin-like growth factor 1 (IGF-1) by the mouse chymase mMCP-4 (25). Therefore, we decided to examine the potential cleavage of this growth factor by HC and hCG.…”