Ding Yingjun, Chen Junxiong, Liu Songlan, Hays Jennifer M, Gu Xiaowu, Wren Jonathan D, Georgescu Constantin, Reuter Darlene N, Liu Beibei, He Furong, Wang Xuejun, Wei Quan, Wang Jie, Subramaniyan Bharathiraja, Wu Zhiping, Kodali Kiran, Reagan Alaina M, Freeman Willard M, Miranti Cindy K, Csiszar Anna, Ungvari Zoltan, Mehla Kamiya, Walters Matthew S, Elliott Michael H, Peng Junmin, Kanie Tomoharu, Papin James F, Hays Franklin A, Zhang Xin A
Stephenson Cancer Center and Departments of Biochemistry & Physiology, Ophthalmology, Comparative Medicine, Cell Biology, Internal Medicine, Neurosurgery, and Oncology Science, University of Oklahoma Health Science Center, Oklahoma City, OK, USA.
Genes & Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
Nat Cardiovasc Res. 2025 Jul 29. doi: 10.1038/s44161-025-00686-2.
Tetraspanins affect metastasis, stemness and angiogenesis, but their roles in inflammation remain to be further clarified. Here we show that endothelial ablation of tetraspanin Cd82 markedly reduces vascular inflammation by mitigating endothelial leakage. Mechanistically, by limiting the anchorages of Cdc42 activator FARP1 and RhoA inhibitor Rnd3 to the plasma membrane (PM), CD82 confines Cdc42 but maintains RhoA activity in endothelial cells, to facilitate endothelium activation. These signaling regulatory effects depend on the ability of CD82 to coalesce and retain accessible cholesterol (AC) at the PM, whereas simvastatin overturns CD82 effects by lowering AC. CD82 supports non-vesicular transfer of AC to the PM through oxysterol-binding protein-related proteins (ORPs). Thus, CD82 and AC promote vascular leakage, whereas statin and ORP inhibitor restrain vascular leakage by decreasing AC. These findings reveal an unconventional anti-inflammation role and mechanism for statin and conceptualize tetraspanin-mediated, AC-mediated and cholesterol transfer-mediated balancing of antagonistic GTPase signaling pathways as regulatory mechanisms for vascular leakage.
四跨膜蛋白影响转移、干性和血管生成，但其在炎症中的作用仍有待进一步阐明。在此我们表明，在内皮细胞中敲除四跨膜蛋白Cd82可通过减轻内皮渗漏显著降低血管炎症。从机制上讲，通过限制Cdc42激活剂FARP1和RhoA抑制剂Rnd3与质膜（PM）的锚定，CD82在内皮细胞中限制Cdc42但维持RhoA活性，以促进内皮细胞活化。这些信号调节作用取决于CD82在质膜上凝聚并保留可及胆固醇（AC）的能力，而辛伐他汀通过降低AC来逆转CD82的作用。CD82通过氧甾醇结合蛋白相关蛋白（ORPs）支持AC向质膜的非囊泡转运。因此，CD82和AC促进血管渗漏，而他汀类药物和ORP抑制剂通过减少AC来抑制血管渗漏。这些发现揭示了他汀类药物的一种非常规抗炎作用和机制，并将四跨膜蛋白介导、AC介导和胆固醇转移介导的拮抗性GTPase信号通路平衡概念化为血管渗漏的调节机制。
