Calpain-dependent Cleavage of N-cadherin Is Involved in the Progression of Post-myocardial Infarction Remodeling [Protein Synthesis and Degradation]

June 2nd, 2014 by Kudo-Sakamoto, Y., Akazawa, H., Ito, K., Takano, J., Yano, M., Yabumoto, C., Naito, A. T., Oka, T., Lee, J.-K., Sakata, Y., Suzuki, J.-i., Saido, T. C., Komuro, I.

Enzymatic proteolysis by calpains, Ca2+-dependent intracellular cysteine proteases, has been implicated in pathological processes such as cellular degeneration or death. Here, we investigated the role of calpain activation in the hearts subjected to myocardial infarction. We produced myocardial infarction in Cast-/- mice deficient for calpastatin, the specific endogenous inhibitory protein for calpains, and Cast+/+ mice. The activity of cardiac calpains in Cast+/+ mice was not elevated within 1 day, but showed a gradual elevation after 7 days following myocardial infarction, which was further pronounced in Cast-/- mice. Although the prevalence of cardiomyocyte death was indistinguishable between Cast-/- and Cast+/+ mice, Cast-/- mice exhibited profound contractile dysfunction and chamber dilatation and showed a significant reduction in survival rate after myocardial infarction, as compared with Cast+/+ mice. Notably, immunofluorescence revealed that, at 28 days after myocardial infarction, calpains were activated in cardiomyocytes exclusively at the border zone, and that Cast-/- mice showed higher intensity and broader extent of calpain activation at the border zone than Cast+/+ mice. In the border zone of Cast-/- mice, pronounced activation of calpains was associated with a decrease in N-cadherin expression and up-regulation of molecular markers for cardiac hypertrophy and fibrosis. In cultured rat neonatal cardiomyocytes, activation of calpains by treatment with ionomycin induced cleavage of N-cadherin, and decreased expression levels of β-catenin and connexin 43, which was attenuated by calpain inhibitor. These results thus demonstrate that activation of calpains disassembles cell-cell adhesion at intercalated discs by degrading N-cadherin, and thereby promotes left ventricular remodeling after myocardial infarction.
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