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CUEDC2通过调节GPX1稳定性来调控心肌细胞的氧化能力。

CUEDC2 modulates cardiomyocyte oxidative capacity by regulating GPX1 stability.

作者信息

Jian Zhao, Liang Bing, Pan Xin, Xu Guang, Guo Sai-Sai, Li Ting, Zhou Tao, Xiao Ying-Bin, Li Ai-Ling

机构信息

Institute of Cardiovascular Surgery, Xinqiao Hospital Third Military Medical University, Chongqing, China.

State Key Laboratory of Proteomics, Institute of Basic Medical Sciences National Center of Biomedical Analysis, Beijing, China.

出版信息

EMBO Mol Med. 2016 Jul 1;8(7):813-29. doi: 10.15252/emmm.201506010. Print 2016 Jul.

DOI:10.15252/emmm.201506010
PMID:27286733
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4931293/
Abstract

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.

摘要

由于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。在此，我们报告含CUE结构域的蛋白CUEDC2在氧化应激诱导的心脏损伤中起关键作用。Cuedc2基因敲除的心肌细胞对氧化应激诱导的细胞死亡表现出更大的抗性。CUEDC2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，并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，CUEDC2促进E3泛素连接酶含三联基序蛋白33（TRIM33）介导抗氧化酶谷胱甘肽过氧化物酶1（GPX1）的泛素化及蛋白酶体依赖性降解。敲除CUEDC2可显著上调心脏中GPX1的蛋白水平。引人注目的是，在体内I/R损伤后，Cuedc2基因敲除小鼠心脏的梗死面积显著减小，并且衰老的Cuedc2基因敲除小鼠心脏功能保留得更好，因为其心脏中的总ROS水平显著降低。我们的结果证明了CUEDC2在心肌细胞死亡调控中的新作用。调控CUEDC2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一种有吸引力的治疗策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a9cc/4931293/27ca6407ed55/EMMM-8-813-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a9cc/4931293/e96452ab5238/EMMM-8-813-g002.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a9cc/4931293/e994d5ff4954/EMMM-8-813-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a9cc/4931293/27ca6407ed55/EMMM-8-813-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a9cc/4931293/e96452ab5238/EMMM-8-813-g002.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a9cc/4931293/4e8c9854d931/EMMM-8-813-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a9cc/4931293/e1cb17677af9/EMMM-8-813-g008.jpg
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