YAP Controls Endothelial Activation and Vascular Inflammation Through TRAF6.
YAP Controls Endothelial Activation and Vascular Inflammation Through TRAF6.
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DOI：
10.1161/circresaha.118.313143
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发表时间：
2018-06-22
影响因子：
20.1
通讯作者：
Hu G
中科院分区：
文献类型：
--
作者：
Lv Y;Kim K;Sheng Y;Cho J;Qian Z;Zhao YY;Hu G;Pan D;Malik AB;Hu G
继发于未受抑制的内皮活化的微血管炎症和内皮功能障碍在脓毒症和器官衰竭的病理生理学中起关键作用。负责抑制内皮细胞过度活化的内在信号传导机制尚未完全了解。确定Yes相关蛋白（雅普）（Hippo通路的主要转录共激活因子）在调节内皮激活和血管炎症的强度和程度中的中心作用。内皮特异性雅普基因敲除小鼠显示内皮细胞中E-选择素和细胞间粘附分子-1的基础表达增加，毛细血管后微静脉中粘附的中性粒细胞数量增加，支气管肺泡灌洗液中中性粒细胞计数增加。这些小鼠的脂多糖激发增强了核因子-κB（NF-κB）活化、内皮粘附蛋白的表达、中性粒细胞和单核细胞粘附至提睾肌小静脉、跨内皮中性粒细胞迁移和肺部炎性损伤。内皮细胞中雅普的缺失也显著增强了盲肠结扎和穿孔诱导的多微生物脓毒症模型中的炎症反应和心血管功能障碍。雅普通过与E3泛素蛋白连接酶Toll样受体信号转导接头肿瘤坏死因子受体相关因子6（TRAF 6）相互作用，使TRAF 6泛素化，从而促进TRAF 6的降解和修饰，抑制NF-κB的活化。内皮细胞中的TRAF 6耗竭挽救了内皮细胞特异性缺失雅普的小鼠中增强的炎症表型。雅普通过阻止TRAF 6介导的NF-κB活化来调节内皮细胞的活化并抑制血管炎症，因此对于限制脓毒症诱导的炎症和器官衰竭的严重程度是必需的。
Microvascular inflammation and endothelial dysfunction secondary to unchecked activation of endothelium plays a critical role in the pathophysiology of sepsis and organ failure. The intrinsic signaling mechanisms responsible for dampening excessive activation of endothelial cells are not completely understood. To determine the central role of Yes-associated protein (YAP), the major transcriptional co-activator of the Hippo pathway, in modulating the strength and magnitude of endothelial activation and vascular inflammation. Endothelial specific YAP knockout mice showed increased basal expression of E-selectin and intercellular adhesion molecule-1 in endothelial cells, a greater number of adherent neutrophils in post-capillary venules and increased neutrophil counts in bronchoalveolar lavage fluid. Lipopolysaccharide challenge of these mice augmented nuclear factor-κB (NF-κB) activation, expression of endothelial adhesion proteins, neutrophil and monocyte adhesion to cremaster muscle venules, transendothelial neutrophil migration, and lung inflammatory injury. Deletion of YAP in endothelial cells also markedly augmented the inflammatory response and cardiovascular dysfunction in a polymicrobial sepsis model induced by cecal ligation and puncture. YAP functioned by interacting with the E3 ubiquitin-protein ligase Toll-like receptor signaling adaptor tumor necrosis factor receptor-associated factor 6 (TRAF6) to ubiquitinate TRAF6, and thus promoted TRAF6 degradation and modification resulting in inhibition of NF-κB activation. TRAF6 depletion in endothelial cells rescued the augmented inflammatory phenotype in mice with endothelial cell specific deletion of YAP. YAP modulates the activation of endothelial cells and suppresses vascular inflammation through preventing TRAF6-mediated NF-κB activation and is hence essential for limiting the severity of sepsis-induced inflammation and organ failure.