CUEDC2 modulates cardiomyocyte oxidative capacity by regulating GPX1 stability.
CUEDC2 modulates cardiomyocyte oxidative capacity by regulating GPX1 stability.
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CUEDC2通过调节GPX1稳定性来调节心肌细胞氧化能力
DOI：
10.15252/emmm.201506010
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发表时间：
2016-07
影响因子：
11.1
通讯作者：
Li AL
中科院分区：
文献类型：
--
作者：
Jian Z;Liang B;Pan X;Xu G;Guo SS;Li T;Zhou T;Xiao YB;Li AL
氧化应激导致的心肌细胞不可逆损失是缺血/再灌注（I/R）损伤和衰老诱导的心肌病后心脏功能障碍的主要原因。在这里，我们报告了CUEDC 2，一种含有CUE结构域的蛋白，在氧化应激诱导的心脏损伤中起着关键作用。Cuedc 2 −/−心肌细胞对氧化应激诱导的细胞死亡表现出更大的抵抗力。CUEDC 2的缺失增强了心肌细胞的抗氧化能力，促进了活性氧（ROS）的清除，随后抑制了信号通路的氧化还原依赖性激活。值得注意的是，CUEDC 2促进E3泛素连接酶三重基序33（TRIM 33）介导的抗氧化酶、谷胱甘肽过氧化物酶1（GPX 1）泛素化和蛋白酶体依赖性降解。CUEDC 2的消融显著上调了心脏GPX 1的蛋白水平。引人注目的是，在体内，I/R损伤后Cuedc 2 −/−心脏的梗死面积显著减少，老年Cuedc 2 −/−小鼠保持了更好的心脏功能，因为它们心脏中的总体ROS水平显著降低。我们的研究结果证明了CUEDC 2在心肌细胞死亡调节中的新作用。操纵CUEDC 2水平可能是促进氧化应激诱导的心脏损伤后心肌细胞存活的有吸引力的治疗策略。
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.