Department of Cardiology, the First Hospital of China Medical University, Shenyang, Liaoning, China.
Key Laboratory of Medical Cell Biology, Ministry of Education; Institute of Translational Medicine, China Medical University; Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, Shenyang, Liaoning, China.
Biomed Pharmacother. 2023 Oct;166:115228. doi: 10.1016/j.biopha.2023.115228. Epub 2023 Aug 7.
As a widely used lipid-lowering drug in clinical practice, atorvastatin is widely recognized for its role in protecting vascular endothelium in the cardiovascular system. However, a clear mechanistic understanding of its action is lacking. Here, we found that atorvastatin counteracted angiotensin II-induced vascular endothelial injury in mice with hypertension. Mechanistically, atorvastatin up-regulated WWP2, a E6AP C-terminus (HECT)-type E3 ubiquitin ligase with an essential role in regulating protein ubiquitination and various biological processes, thereby rescuing vascular endothelial injury. By ubiquitinating ATP5A (ATP synthase mitochondrial F1 complex subunit alpha), WWP2 degraded ATP5A via the proteasome pathway, stabilizing Bcl-2/Bax in the mitochondrial pathway of apoptosis. Moreover, atorvastatin further ameliorated death of vascular endothelial cells and improved vascular endothelial functions under WWP2 overexpression, whereas WWP2 knockout abrogated these beneficial effects of atorvastatin. Furthermore, we generated endothelial cell-specific WWP2 knockout mice, and this WWP2-mediated mechanism was faithfully recapitulated in vivo. Thus, we propose that activation of a WWP2-dependent pathway that is pathologically repressed in damaged vascular endothelium under hypertension is a major mechanism of atorvastatin. Our findings are also pertinent to develop novel therapeutic strategies for vascular endothelial injury-related cardiovascular diseases.
阿托伐他汀作为临床实践中广泛使用的降脂药物，因其在心血管系统中保护血管内皮的作用而被广泛认可。然而，其作用的明确机制尚不清楚。在这里，我们发现在高血压小鼠中，阿托伐他汀可拮抗血管紧张素 II 诱导的血管内皮损伤。在机制上，阿托伐他汀上调了 WWP2，一种 E6AP C 端（HECT）-型 E3 泛素连接酶，在调节蛋白泛素化和各种生物过程中起关键作用，从而挽救血管内皮损伤。通过泛素化 ATP5A（线粒体 F1 复合物亚基 alpha 的 ATP 合酶），WWP2 通过蛋白酶体途径降解 ATP5A，稳定线粒体凋亡途径中的 Bcl-2/Bax。此外，阿托伐他汀在过表达 WWP2 时进一步改善了血管内皮细胞的死亡和血管内皮功能，而 WWP2 敲除则消除了阿托伐他汀的这些有益作用。此外，我们还生成了内皮细胞特异性 WWP2 敲除小鼠，并且该 WWP2 介导的机制在体内得到了准确的再现。因此，我们提出，在高血压下受损血管内皮中病理性抑制的 WWP2 依赖性途径的激活是阿托伐他汀的主要作用机制。我们的发现也与开发与血管内皮损伤相关的心血管疾病的新型治疗策略有关。
