YAP Controls Endothelial Activation and Vascular Inflammation Through TRAF6

Yang Lv, Kyungho Kim, Yue Sheng, Jaehyung Cho, Zhijian Qian, You Yang Zhao, Gang Hu, Duojia Pan Ph.D., Asrar B. Malik, Guochang Hu

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

RATIONALE: 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. OBJECTIVE: 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. METHODS AND RESULTS: 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. CONCLUSIONS: 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.

Original languageEnglish (US)
Pages (from-to)43-56
Number of pages14
JournalCirculation Research
Volume123
Issue number1
DOIs
StatePublished - Jun 22 2018

Fingerprint

Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
Blood Vessels
Inflammation
Endothelial Cells
Neutrophils
Proteins
Sepsis
Venules
Transendothelial and Transepithelial Migration
Abdominal Muscles
E-Selectin
Ubiquitin-Protein Ligases
Toll-Like Receptors
Bronchoalveolar Lavage Fluid
Lung Injury
Intercellular Adhesion Molecule-1
Punctures
Knockout Mice
Endothelium
Ligation

Keywords

  • acute lung injury
  • E-selectin
  • endothelial cells
  • neutrophils
  • sepsis
  • ubiquitination

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Lv, Y., Kim, K., Sheng, Y., Cho, J., Qian, Z., Zhao, Y. Y., ... Hu, G. (2018). YAP Controls Endothelial Activation and Vascular Inflammation Through TRAF6. Circulation Research, 123(1), 43-56. https://doi.org/10.1161/CIRCRESAHA.118.313143

YAP Controls Endothelial Activation and Vascular Inflammation Through TRAF6. / Lv, Yang; Kim, Kyungho; Sheng, Yue; Cho, Jaehyung; Qian, Zhijian; Zhao, You Yang; Hu, Gang; Pan Ph.D., Duojia; Malik, Asrar B.; Hu, Guochang.

In: Circulation Research, Vol. 123, No. 1, 22.06.2018, p. 43-56.

Research output: Contribution to journalArticle

Lv, Y, Kim, K, Sheng, Y, Cho, J, Qian, Z, Zhao, YY, Hu, G, Pan Ph.D., D, Malik, AB & Hu, G 2018, 'YAP Controls Endothelial Activation and Vascular Inflammation Through TRAF6', Circulation Research, vol. 123, no. 1, pp. 43-56. https://doi.org/10.1161/CIRCRESAHA.118.313143
Lv, Yang ; Kim, Kyungho ; Sheng, Yue ; Cho, Jaehyung ; Qian, Zhijian ; Zhao, You Yang ; Hu, Gang ; Pan Ph.D., Duojia ; Malik, Asrar B. ; Hu, Guochang. / YAP Controls Endothelial Activation and Vascular Inflammation Through TRAF6. In: Circulation Research. 2018 ; Vol. 123, No. 1. pp. 43-56.
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AU - Zhao, You Yang

AU - Hu, Gang

AU - Pan Ph.D., Duojia

AU - Malik, Asrar B.

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AB - RATIONALE: 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. OBJECTIVE: 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. METHODS AND RESULTS: 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. CONCLUSIONS: 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.

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