Nguyen Tung D, Rao Mihir K, Dhyani Shaiva P, Banks Justin M, Winek Michael A, Michalkiewicz Julka, Lee Monica Y
bioRxiv. 2023 Nov 14:2023.11.10.566598. doi: 10.1101/2023.11.10.566598.
Endothelial cells (ECs) form the innermost lining of the vasculature and serve a pivotal role in preventing age-related vascular disease. Endothelial health relies on the proper nucleocytoplasmic shuttling of transcription factors via nuclear pore complexes (NPCs). Emerging studies report NPC degradation with natural aging, suggesting impaired nucleocytoplasmic transport in age-related EC dysfunction. We herein identify nucleoporin93 (Nup93), a crucial structural NPC protein, as an indispensable player for vascular protection. Endothelial Nup93 protein levels are significantly reduced in the vasculature of aged mice, paralleling observations of Nup93 loss when using models of endothelial aging. Mechanistically, we find that loss of Nup93 impairs NPC transport, leading to the nuclear accumulation of Yap and downstream inflammation. Collectively, our findings indicate maintenance of endothelial Nup93 as a key determinant of EC health, where aging targets endothelial Nup93 levels to impair NPC function as a novel mechanism for EC senescence and vascular aging.
内皮细胞（ECs）构成血管的最内层，在预防与年龄相关的血管疾病中起关键作用。内皮健康依赖于转录因子通过核孔复合体（NPCs）进行适当的核质穿梭。新出现的研究报告称，随着自然衰老，NPC会发生降解，这表明在与年龄相关的内皮细胞功能障碍中核质运输受损。我们在此确定核孔蛋白93（Nup93），一种关键的结构性NPC蛋白，是血管保护中不可或缺的因素。老年小鼠血管中的内皮Nup93蛋白水平显著降低，这与使用内皮衰老模型时观察到的Nup93缺失情况相似。从机制上讲，我们发现Nup93的缺失会损害NPC运输，导致Yap在细胞核内积累并引发下游炎症。总的来说，我们的研究结果表明，维持内皮Nup93是内皮细胞健康的关键决定因素，衰老会靶向内皮Nup93水平，损害NPC功能，这是内皮细胞衰老和血管衰老的一种新机制。
