From the Department of Anesthesiology (Y.L., Guochang Hu).
University of Illinois College of Medicine, Chicago; Department of Pharmacology, Nanjing Medical University, Jiangsu, China (Y.L., Gang Hu).
Circ Res. 2018 Jun 22;123(1):43-56. doi: 10.1161/CIRCRESAHA.118.313143. Epub 2018 May 23.
Microvascular inflammation and endothelial dysfunction secondary to unchecked activation of endothelium play 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 YAP (Yes-associated protein), the major transcriptional coactivator 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 ICAM (intercellular adhesion molecule)-1 in endothelial cells, a greater number of adherent neutrophils in postcapillary venules and increased neutrophil counts in bronchoalveolar lavage fluid. Lipopolysaccharide challenge of these mice augmented NF-κB (nuclear factor-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 TLR (Toll-like receptor) signaling adaptor TRAF6 (tumor necrosis factor receptor-associated factor 6) 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.
不受控制的内皮细胞激活引起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着关键作用。负责抑制内皮细胞过度激活的内在信号机制尚不完全清楚。
确定 Hippo 通路的主要转录共激活因子 YAP（Yes 相关蛋白）在调节内皮细胞激活和血管炎症的强度和幅度中的核心作用。
内皮细胞特异性 YAP 敲除小鼠表现出内皮细胞中 E-选择素和 ICAM（细胞间黏附分子）-1的基础表达增加，毛细血管后静脉中附着的中性粒细胞增多，支气管肺泡灌洗液中的中性粒细胞计数增加。这些小鼠的脂多糖（LPS）挑战增强了 NF-κB（核因子-κB）的激活、内皮黏附蛋白的表达、中性粒细胞和单核细胞对肠系膜静脉的黏附、跨内皮中性粒细胞迁移以及肺部炎症损伤。内皮细胞中 YAP 的缺失也明显增强了由盲肠结扎和穿刺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。YAP 通过与 E3 泛素蛋白连接酶 TLR（Toll 样受体）信号衔接 TRAF6（肿瘤坏死因子受体相关因子 6）相互作用发挥作用，从而泛素化 TRAF6，促进 TRAF6 降解和修饰，从而抑制 NF-κB 激活。内皮细胞中 TRAF6 的缺失挽救了内皮细胞特异性缺失 YAP 的小鼠中增强的炎症表型。
YAP 通过防止 TRAF6 介导的 NF-κB 激活来调节内皮细胞的激活并抑制血管炎症，因此对于限制脓毒症引起的炎症和器官衰竭的严重程度至关重要。
