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.
Institute of Cardiovascular Surgery, Xinqiao Hospital Third Military Medical University, Chongqing, China.
Zhao
Z
Jian
State Key Laboratory of Proteomics, Institute of Basic Medical Sciences National Center of Biomedical Analysis, Beijing, China.
Bing
B
Liang
State Key Laboratory of Proteomics, Institute of Basic Medical Sciences National Center of Biomedical Analysis, Beijing, China.
Xin
X
Pan
State Key Laboratory of Proteomics, Institute of Basic Medical Sciences National Center of Biomedical Analysis, Beijing, China.
Guang
G
Xu
State Key Laboratory of Proteomics, Institute of Basic Medical Sciences National Center of Biomedical Analysis, Beijing, China.
Sai-Sai
SS
Guo
State Key Laboratory of Proteomics, Institute of Basic Medical Sciences National Center of Biomedical Analysis, Beijing, China.
Ting
T
Li
State Key Laboratory of Proteomics, Institute of Basic Medical Sciences National Center of Biomedical Analysis, Beijing, China.
Tao
T
Zhou
Institute of Cardiovascular Surgery, Xinqiao Hospital Third Military Medical University, Chongqing, China xiaoyb@tmmu.edu.cn alli@ncba.ac.cn.
Ying-Bin
0000-0003-1854-8982
YB
Xiao
State Key Laboratory of Proteomics, Institute of Basic Medical Sciences National Center of Biomedical Analysis, Beijing, China xiaoyb@tmmu.edu.cn alli@ncba.ac.cn.
Ai-Ling
AL
Li
D000818:Animals; D005979:Glutathione Peroxidase / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000473:pathology; D032383:Myocytes, Cardiac / Q000502:physiology*; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction; D000094765:Glutathione Peroxidase GPX1
C576361:CUEDC2 protein, mouse; D017382:Reactive Oxygen Species; D012097:Repressor Proteins; D005979:Glutathione Peroxidase; D000094765:Glutathione Peroxidase GPX1; C000722068:Gpx1 protein, mouse
CUEDC2; GPX1; ageing‐induced cardiomyopathy; antioxidant capacity; ischemia/reperfusion injury