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.

缺血心肌中铜代谢 MURR 结构域 1 (COMMD1) 增加，同时收缩力受到抑制。心肌细胞特异性删除 COMMD1 可以保留心肌收缩功能，以应对相同的缺血性损伤。本研究的目的是检验 COMMD1 心肌中的心肌细胞保护负责心脏响应缺血性损伤的功能保存的假设。缺血性损伤后，心肌细胞特异性 COMMD1 缺失心肌中的心肌细胞明显多于 WT 对照。与对照组相比，COMMD1 缺失心肌中细胞凋亡的显着抑制与心肌细胞的保存同时发生。在寻找 COMMD1 缺失抗凋亡作用的机制时，我们发现抗凋亡 Bcl-2 mRNA 和蛋白表达上调，促凋亡 Bax mRNA 和蛋白表达下调。关键转录因子 RelA 维持 Bcl-2 和 Bax 之间的高比例以发挥抗凋亡作用，它受到缺血的抑制，但在 COMMD1 缺失的心肌中得到了挽救。由于 COMMD1 关键参与 RelA 泛素化和降解，因此此处获得的数据表明 COMMD1 缺失导致缺血心肌中 RelA 保存，促进 Bcl-2 抗凋亡途径并抑制 Bax 促凋亡途径，并共同导致保护心肌细胞免受缺血诱导的细胞凋亡。