Abstract 14334: Calpastatin Deficiency Exacerbates Calpain-dependent Progression of Left Ventricular Remodeling After Myocardial Infarction
The calpains are Ca2+-dependent cysteine proteases, and play a regulatory role in cellular functions such as cytoskeletal remodeling, cell cycle regulation, membrane repair, and cell degeneration and death. Especially,calpains mediate Ca2+ overload-induced proteolysis, and are implicated in the execution of myocardial cell death during ischemia-reperfusion. However, the consequences of calpain activation after myocardial infarction (MI) remain to be fully elucidated in an in vivo context. To elucidate the role of calpains in MI hearts, we produced MI in wild-type (WT) mice and calpastatin-deficient (CAST KO) mice, because calpastatin is the sole and specific endogenous inhibitory protein for calpains. Immunoblot analysis using an antibody for calpains-cleaved αII-spectrin revealed that the activity of cardiac calpains in WT mice was not elevated within 1 day, but showed a gradual elevation after 7 days after MI, which was further pronounced in CAST KO mice. The prevalence of cardiomyocyte apoptosis was significantly increased after MI, but indistinguishable between WT and CAST KO mice. However, CAST KO mice exhibited profound contractile dysfunction and chamber dilatation at 28 days after MI, as compared with WT mice. Immunofluorescence revealed that, at 28 days after MI, calpains were activated in cardiomyocytes exclusively at the peri-infarct zone, where N-cadherin expression was decreased in a manner reciprocal to increased activation of calpains at intercalated discs. In cultured rat neonatal cardiomyocytes, treatment with the Ca2+ ionophore ionomycin induced activation of calpains and cleavage of N-cadherin, both of which were attenuated by treatment with the calpain inhibitor III. In conclusion, these results suggest that activation of calpains may disassemble cell-cell adhesion at intercalated discs by degrading N-cadherin, and thereby promote left ventricular remodeling after MI.
- © 2013 by American Heart Association, Inc.