Jiang Bin, Bai Fan, Hu Yunfu, Ren Yu, Su Yuan, Song Wanxuan, Xie Kunxin, Wang Dongdong, Pan Junlu, Liu Yuying, Feng Yuxin, Li Xiaoyu, Zhang Hanwen, Zhu Xudong, Bai Hui, Yang Qing, Ben Jingjing, Chen Qi
Department of Pathophysiology, Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, China.
Department of Forensic Medicine, Nanjing Medical University, Nanjing, China.
Nat Commun. 2025 May 10;16(1):4365. doi: 10.1038/s41467-025-59644-y.
Many important vascular diseases including neointimal hyperplasia and atherosclerosis are characterized by the endothelial cell (EC) injury-initiated pathological vascular remodeling. However, the endogenous regulatory mechanisms underlying it are not fully understood. The present study investigates regulatory role of major vault protein (MVP) in the pathogenesis of vascular remodeling via controlling EC injury. By generating male murine vascular disease models, we find that ablation of endothelial MVP increases neointima formation and promotes atherosclerosis. Mechanistically, MVP directly binds with Parkin and inhibits the ubiquitination and proteasomal degradation of Parkin by dissociating the E3 ligase NEDD4L from Parkin, leading to activation of Parkin-mediated mitophagy pathway in the EC. Genetic modulation of endothelial MVP and Parkin influences the mitophagy, apoptosis, and neointima formation. These results demonstrate that MVP acts as an intracellular regulator promoting Parkin-mediated mitophagy. Our findings suggest that MVP/NEDD4L/Parkin axis may serve as the therapeutic target for treating intimal hyperplasia and atherosclerosis.
包括新生内膜增生和动脉粥样硬化在内的许多重要血管疾病，其特征是由内皮细胞（EC）损伤引发的病理性血管重塑。然而，其潜在的内源性调节机制尚未完全明确。本研究通过控制内皮细胞损伤，探讨主要穹窿蛋白（MVP）在血管重塑发病机制中的调节作用。通过构建雄性小鼠血管疾病模型，我们发现内皮细胞MVP缺失会增加新生内膜形成并促进动脉粥样硬化。机制上，MVP直接与帕金蛋白结合，通过使E3连接酶NEDD4L与帕金蛋白解离，抑制帕金蛋白的泛素化和蛋白酶体降解，从而激活内皮细胞中帕金蛋白介导的线粒体自噬途径。对内皮细胞MVP和帕金蛋白的基因调控会影响线粒体自噬、细胞凋亡和新生内膜形成。这些结果表明，MVP作为一种细胞内调节因子，可促进帕金蛋白介导的线粒体自噬。我们的研究结果提示，MVP/NEDD4L/帕金蛋白轴可能成为治疗内膜增生和动脉粥样硬化的治疗靶点。
