Cardiomyocyte-Specific COMMD1 Deletion Suppresses Ischemia-Induced Myocardial Apoptosis.

Abstract

Copper metabolism MURR domain 1 (COMMD1) increases in ischemic myocardium along with suppressed contractility. Cardiomyocyte-specific deletion of COMMD1 preserved myocardial contractile function in response to the same ischemic insult. This study was undertaken to test the hypothesis that cardiomyocyte protection in COMMD1 myocardium is responsible for the functional preservation of the heart in response to ischemic insult. After ischemic insult, there were significantly more cardiomyocytes in the cardiomyocyte-specific COMMD1 deletion myocardium than that in WT controls. This preservation of cardiomyocytes was paralleled by a significant suppression of apoptosis in the COMMD1 deletion myocardium compared to controls. In searching for the mechanistic understanding of the anti-apoptotic effect of COMMD1 deletion, we found the anti-apoptotic Bcl-2 mRNA and protein expression were upregulated and the pro-apoptotic Bax mRNA and protein expression were downregulated. The critical transcription factor RelA, maintaining a high ratio between Bcl-2 and Bax for anti-apoptotic action, was suppressed by ischemia, but was rescued in the COMMD1 deletion myocardium. Because COMMD1 is critically involved in RelA ubiquitination and degradation, the data obtained here demonstrate that COMMD1 deletion leads to RelA preservation in ischemic myocardium, promoting the Bcl-2 anti-apoptotic pathway and suppressing the Bax pro-apoptotic pathway, and in combination, leading to protection of cardiomyocytes from ischemia-induced apoptosis.