c-Abl regulates YAPY357 phosphorylation to activate endothelial atherogenic responses to disturbed flow
Bochuan Li, … , Yi Zhu, Ding Ai
Bochuan Li, … , Yi Zhu, Ding Ai
Published January 10, 2019
Citation Information: J Clin Invest. 2019;129(3):1167-1179. https://doi.org/10.1172/JCI122440.
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Research Article Vascular biology

c-Abl regulates YAPY357 phosphorylation to activate endothelial atherogenic responses to disturbed flow

Abstract

Local flow patterns determine the uneven distribution of atherosclerotic lesions. This research aims to elucidate the mechanism of regulation of nuclear translocation of Yes-associated protein (YAP) under oscillatory shear stress (OSS) in the atheroprone phenotype of endothelial cells (ECs). We report here that OSS led to tyrosine phosphorylation and strong, continuous nuclear translocation of YAP in ECs that is dependent on integrin α5β1 activation. YAP overexpression in ECs blunted the anti-atheroprone effect of an integrin α5β1–blocking peptide (ATN161) in Apoe–/– mice. Activation of integrin α5β1 induced tyrosine, but not serine, phosphorylation of YAP in ECs. Blockage of integrin α5β1 with ATN161 abolished the phosphorylation of YAP at Y357 induced by OSS. Mechanistic studies showed that c-Abl inhibitor attenuated the integrin α5β1–induced YAP tyrosine phosphorylation. Furthermore, the phosphorylation of c-Abl and YAPY357 was significantly increased in ECs in atherosclerotic vessels of mice and in human plaques versus normal vessels. Finally, bosutinib, a tyrosine kinase inhibitor, markedly reduced the level of YAPY357 and the development of atherosclerosis in Apoe–/– mice. The c-Abl/YAPY357 pathway serves as a mechanism for the activation of integrin α5β1 and the atherogenic phenotype of ECs in response to OSS, and provides a potential therapeutic strategy for atherogenesis.

Authors

Bochuan Li, Jinlong He, Huizhen Lv, Yajin Liu, Xue Lv, Chenghu Zhang, Yi Zhu, Ding Ai

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Figure 4

Tyr357 phosphorylation of YAP induced endothelial activation in vitro and in vivo.

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Tyr357 phosphorylation of YAP induced endothelial activation in vitro an...
(A and B) HUVECs were infected with indicated adenoviruses for 24 hours with or without exposure to OSS or ST for another 6 hours. Western blot analysis of protein level of VCAM-1. Data are mean ± SEM, *P < 0.05 (2-way ANOVA with Bonferroni multiple comparison post hoc test), n = 6. (C and D) HUVECs were infected with the indicated adenovirus for 24 hours with or without OSS. THP-1 cells were labeled with fluorescence dye, then cell adhesion assay was performed. Representative images of adhesive cells. Scale bar: 500 μm. Cell number from 5 random fields with ×10 objective was counted in each well. The number of adhesive cells was normalized to that of HUVECs with Ad-GFP infection. Data are mean ± SEM, *P < 0.05 (2-way ANOVA with Bonferroni multiple comparison post hoc test), n = 5. (E) Male Apoe–/– mice underwent partial ligation of the carotid artery. During the ligation, carotid arteries were infused with the indicated adenovirus. Shows enface GFP and immunofluorescence staining of the expression of VCAM-1 in ECs of the carotid artery of mice. Scale bar: 20 μm. (F) Quantification of relative fluorescent intensity of VCAM-1. Data are mean ± SEM, *P < 0.05 (Student’s t test), n = 6 mice.