YAP Controls Endothelial Activation and Vascular Inflammation Through TRAF6

Lv, Y.; Kim, K.; Sheng, Y.; Cho, J.; Qain, Z.; Zhao, Y. Y.; Hu, G.; Pan, D.; Malik, A. B.; Hu, G.

Circ Res. 2018 May 26

Abstract

Rationale: 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. Objective: 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. Methods and Results: 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-small ka, CyrillicB (NF-small ka, CyrillicB) 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-small ka, CyrillicB activation. TRAF6 depletion in endothelial cells rescued the augmented inflammatory phenotype in mice with endothelial cell specific deletion of YAP. Conclusions: YAP modulates the activation of endothelial cells and suppresses vascular inflammation through preventing TRAF6-mediated NF-small ka, CyrillicB activation, and is hence essential for limiting the severity of sepsis-induced inflammation and organ failure.

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