HRD1 prevents atherosclerosis-mediated endothelial cell apoptosis by promoting LOX-1 degradation
HRD1 prevents atherosclerosis-mediated endothelial cell apoptosis by promoting LOX-1 degradation
复制标题
HRD1 通过促进 LOX-1 降解来防止动脉粥样硬化介导的内皮细胞凋亡
DOI：
10.1080/15384101.2020.1754561
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发表时间：
2020-04-20
期刊：
影响因子：
4.3
通讯作者：
Su, Dongming
中科院分区：
文献类型：
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作者：
Li, Qingguo;Xuan, Wenying;Su, Dongming
摘要 3-羟基-3-甲基戊二酰还原酶降解（HRD1）是一种 E3 泛素连接酶，可以保护心脏结构和功能，但其在内皮功能障碍和动脉粥样硬化（AS）中的作用尚不清楚。本研究的目的是探讨HRD1在AS中的作用和生物学功能。动脉粥样硬化内膜中 HRD1 表达显着降低，ox-LDL 导致内皮细胞 (EC) 中 HRD1 水平降低。 HRD1的强制表达抑制了ox-LDL诱导的内皮细胞凋亡。转录因子KLF2特异性结合HRD1启动子并正向调节HRD1的表达。 KLF2 上调可以逆转 ox-LDL 处理的 EC 中 HRD1 水平的下降。进一步分析表明，HRD1与LOX-1相互作用，促进LOX-1被蛋白酶体泛素化和降解。 LOX-1的缺失减弱了HRD1下调诱导的EC细胞凋亡。普伐他汀通过 KLF2 依赖性机制保护 EC 免受损伤，可以剂量依赖性地增强暴露于 ox-LDL 的 EC 中的 HRD1 表达。有趣的是，HRD1 的干扰消除了普伐他汀的细胞保护作用。总的来说，我们的数据表明，HRD1 表达减少会导致 EC 细胞凋亡，而 HRD1 表达的恢复可能代表人类 AS 治疗的新策略。
ABSTRACT The 3-hydroxy-3-methylglutaryl reductase degradation (HRD1) is an E3 ubiquitin ligase that can preserve heart structure and function, but its role in endothelial dysfunction and atherosclerosis (AS) is unclear. The aim of this study was to explore the role and biological function of HRD1 in AS. HRD1 expression was significantly decreased in atherosclerotic intima and ox-LDL led to a decrease of HRD1 level in endothelial cells (ECs). Forced expression of HRD1 inhibited the endothelial apoptosis induced by ox-LDL. The transcription factor KLF2 specifically bound to the HRD1 promoter and positively regulated HRD1 expression. KLF2 up-regulation could reverse the decrease of HRD1 level in ECs treated with ox-LDL. Further analysis showed that HRD1 interacted with LOX-1 and promoted ubiquitination and degradation of LOX-1 by the proteasome. Deletion of LOX-1 attenuated the ECs apoptosis induced by HRD1 downregulation. Pravastatin, which protected EC from damage via a KLF2-dependent mechanism, could dose-dependently enhanced HRD1 expression in EC exposed to ox-LDL. Interestingly, interference of HRD1 abolished the cytoprotective effect of pravastatin. Collectively, our data indicate that decreased HRD1 expression leads to apoptosis of ECs and restoration of HRD1 expression could represent a novel strategy for human AS therapy.