CUEDC2 modulates cardiomyocyte oxidative capacity by regulating GPX1 stability

The irreversible loss of cardiomyocytes due to oxidative stress is the main cause of heart dysfunction following ischemia/reperfusion (I/R) injury and ageing‐induced cardiomyopathy. Here, we report that CUEDC2, a CUE domain‐containing protein, plays a critical role in oxidative stress‐induced cardiac injury. Cuedc2 (−/−) cardiomyocytes exhibited a greater resistance to oxidative stress‐induced cell death. Loss of CUEDC2 enhanced the antioxidant capacity of cardiomyocytes, promoted reactive oxygen species (ROS) scavenging, and subsequently inhibited the redox‐dependent activation of signaling pathways. Notably, CUEDC2 promoted E3 ubiquitin ligases tripartite motif‐containing 33 (TRIM33)‐mediated the antioxidant enzyme, glutathione peroxidase 1 (GPX1) ubiquitination, and proteasome‐dependent degradation. Ablation of CUEDC2 upregulated the protein level of GPX1 in the heart significantly. Strikingly, in vivo, the infarct size of Cuedc2 (−/−) heart was significantly decreased after I/R injury, and aged Cuedc2 (−/−) mice preserved better heart function as the overall ROS levels in their hearts were significantly lower. Our results demonstrated a novel role of CUEDC2 in cardiomyocyte death regulation. Manipulating CUEDC2 level might be an attractive therapeutic strategy for promoting cardiomyocyte survival following oxidative stress‐induced cardiac injury.