FAT10 attenuates hypoxia-induced cardiomyocyte apoptosis by stabilizing caveolin-3
FAT10 attenuates hypoxia-induced cardiomyocyte apoptosis by stabilizing caveolin-3
复制标题
FAT10 通过稳定 Caveolin-3 减轻缺氧诱导的心肌细胞凋亡
DOI：
10.1016/j.yjmcc.2018.02.008
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发表时间：
2018-03-01
影响因子：
5
通讯作者：
Hong, Kui
中科院分区：
文献类型：
--
作者：
Zhou, Qiongqiong;Peng, Xiaogang;Hong, Kui
FAT 10是泛素样修饰蛋白家族的成员，在缺氧/缺血损伤中起心脏保护作用。Caveolin-3（Cav-3）是肌细胞特异性的Caveolin家族成员，参与心肌细胞凋亡。然而，缺血心肌细胞中FAT 10和Cav-3之间的联系尚不清楚。在本研究中，我们发现FAT 10和Cav-3在缺血心肌组织和缺氧心肌细胞中均上调。此外，我们的研究结果表明，FAT 10通过增加Cav-3的表达来抑制缺氧诱导的心肌细胞凋亡。重要的是，在心肌梗死后，FAT 10的敲除通过减少Cav-3表达而加重心功能障碍并增加心肌细胞凋亡。此外，Cav-3在心肌细胞中被泛素蛋白酶体系统（UPS）降解。从机制上讲，我们发现FAT 10通过抑制心肌细胞中泛素化介导的降解来稳定Cav-3的表达。总之，这些发现揭示了FAT 10通过稳定Cav-3在保护缺血诱导的损伤中的新作用，为FAT 10/Cav-3轴可能成为缺血性心脏病患者的潜在治疗靶点提供了证据。
FAT10, a member of the ubiquitin-like-modifier family of proteins, plays a cardioprotective role in response to hypoxic/ischemic injury. Caveolin-3 (Cav-3), a muscle-specific caveolin family member, is involved in cardiomyocyte apoptosis. However, the link between FAT10 and Cav-3 in ischemic cardiomyocytes is unclear. In the present study, we found that both FAT10 and Cav-3 were upregulated in ischemic myocardial tissues and in hypoxic cardiomyocytes. Furthermore, our results demonstrated that FAT10 inhibits hypoxia-induced cardiomyocyte apoptosis by increasing Cav-3 expression. Importantly, following myocardial infarction, knockout of FAT10 aggravated cardiac dysfunction and increased cardiomyocyte apoptosis by reducing Cav-3 expression. Additionally, Cav-3 was degraded by the ubiquitin proteasome system (UPS) in cardiomyocytes. Mechanistically, we found that FAT10 stabilizes Cav-3 expression by inhibiting ubiquitination-mediated degradation in cardiomyocytes. Together, these findings revealed a novel role of FAT10 in protection against ischemia-induced injury via stabilization of Cav-3, providing evidence that the FAT10/Cav-3 axis may be a potential therapeutic target for patients with ischemic heart conditions.