Wang Cong, Liu Jijia, Hou Xuyang, Guan Qing, Zhou Huiling, Luo Yong, Jin Wancun, Bai Fan, Liu Lijun, Wang Jian, Xie Li, Li Feng, Liu Haidan
Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China.
Clinical Center for Gene Diagnosis and Therapy, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China.
Cell Biol Toxicol. 2025 May 30;41(1):92. doi: 10.1007/s10565-025-10045-3.
Ubiquitin-proteasome system (UPS) is a major degradation system that maintains cardiac proteostasis, thus displaying an indispensable role in coronary artery disease, including myocardial infarction (MI). However, the function and mechanism of ubiquitin ligases in MI remain unclarified. In this study, we reported that cIAP2 protein, an E3 ubiquitin ligase, was downregulated in MI tissue and oxygen-glucose deprivation (OGD)-treated cardiomyocytes (CMs). cIAP2 depletion promoted OGD-induced injury and apoptosis in CMs, while adeno-associated virus (AAV) serotype 9 mediated-cardiac specific cIAP2 overexpression inhibited myocardial injury in MI mice. Moreover, we identified IGF2BP2 as a novel substrate of cIAP2. Mechanistically, cIAP2 downregulation inhibited IGF2BP2 ubiquitination and proteasomal degradation, leading to the upregulation of IGF2BP2 protein, which subsequently enhanced OGD-induced injury and apoptosis by stabilizing BAX mRNA in an mA-dependent manner. In addition, our results showed that CWI1-2, a small molecule inhibitor of IGF2BP2, alleviated myocardial injury in MI mice by inhibiting cardiomyocyte apoptosis. Altogether, our results indicate that cIAP2 is a ubiquitin E3 ligase of IGF2BP2. The downregulation of cIAP2 protein aggravates OGD-induced apoptosis and oxidative damage in CMs via IGF2BP2/BAX axis. These findings provide a potential therapeutic target for reducing cardiomyocyte loss in MI.
泛素-蛋白酶体系统（UPS）是维持心脏蛋白质稳态的主要降解系统，因此在包括心肌梗死（MI）在内的冠状动脉疾病中发挥着不可或缺的作用。然而，泛素连接酶在心肌梗死中的功能和机制仍不清楚。在本研究中，我们报道E3泛素连接酶cIAP2蛋白在MI组织和氧-葡萄糖剥夺（OGD）处理的心肌细胞（CMs）中表达下调。cIAP2缺失促进了OGD诱导的CMs损伤和凋亡，而腺相关病毒（AAV）血清型9介导的心脏特异性cIAP2过表达抑制了MI小鼠的心肌损伤。此外，我们确定IGF2BP2是cIAP2的一种新底物。机制上，cIAP2下调抑制了IGF2BP2的泛素化和蛋白酶体降解，导致IGF2BP2蛋白上调，随后通过以mA依赖的方式稳定BAX mRNA增强了OGD诱导的损伤和凋亡。此外，我们的结果表明，IGF2BP2的小分子抑制剂CWI1-2通过抑制心肌细胞凋亡减轻了MI小鼠的心肌损伤。总之，我们的结果表明cIAP2是IGF2BP2的泛素E3连接酶。cIAP2蛋白的下调通过IGF2BP2/BAX轴加重了OGD诱导的CMs凋亡和氧化损伤。这些发现为减少MI中心肌细胞损失提供了一个潜在的治疗靶点。
