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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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 2

EC specific YAP overexpression blunts the atheroprotective effect of integrin α5β1 blockage.

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EC specific YAP overexpression blunts the atheroprotective effect of int...
EC-YAPtgApoe–/– and YAPfloxApoe–/– mice were fed a WTD for 4 weeks, during which mice were intraperitoneally injected with scramble peptide (NC) or ATN161 (100 mg/kg) every 3 days. (A) Oil Red O staining of aortas. Scale bar: 4 mm. (B) Plaque area as a percentage of total area. AA, aortic arch; TA, thoracic aorta; NS, not significant. Data are mean ± SEM. YAPfloxApoe–/– + NC (n = 8), YAPfloxApoe–/– + ATN161 (n = 7), EC-YAPtgApoe–/– + NC (n = 5), EC-YAPtgApoe–/– + ATN161 (n = 6). *P < 0.05 (2-way ANOVA with Bonferroni multiple comparison post hoc test). (C–E) HE, Oil Red O, and Mac3 immunofluorescence staining of aortic roots. White dashed line indicates the size of plaque. Quantification of plaque size, Oil Red O–positive area in plaque and Mac3-positive area. Data are mean ± SEM. YAPfloxApoe–/– + NC (n = 8), YAPfloxApoe–/– + ATN161 (n = 7), EC-YAPtgApoe–/– + NC (n = 5), EC-YAPtgApoe–/– + ATN161 (n = 6). *P < 0.05 (2-way ANOVA with Bonferroni multiple comparison post hoc test). NS, not significant. Scale bars: 100 μm. (F) Plasma levels of triglycerides (TG), total cholesterol (CHO), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C). Data are mean ± SEM. YAPfloxApoe–/– + NC (n = 13), YAPfloxApoe–/– + ATN161 (n = 12), EC-YAPtgApoe–/– + NC (n = 10), EC-YAPtgApoe–/– + ATN161 (n = 11).