c-Abl regulates YAP(Y357) phosphorylation to activate endothelial atherogenic responses to disturbed flow

摘要

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 alpha 5 beta 1 activation. YAP overexpression in ECs blunted the anti-atheroprone effect of an integrin alpha 5 beta 1-blocking peptide (ATN161) in Apoe(-/-) mice. Activation of integrin alpha 5 beta 1 induced tyrosine, but not serine, phosphorylation of YAP in ECs. Blockage of integrin alpha 5 beta 1 with ATN161 abolished the phosphorylation of YAP at Y-357 induced by OSS. Mechanistic studies showed that c-Abl inhibitor attenuated the integrin alpha 5 beta 1-induced YAP tyrosine phosphorylation. Furthermore, the phosphorylation of c-Abl and YAP(Y357) 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 YAP(Y357) and the development of atherosclerosis in Apoe(-/-) mice. The c-Abl/YAP(Y357) pathway serves as a mechanism for the activation of integrin alpha 5 beta 1 and the atherogenic phenotype of ECs in response to OSS, and provides a potential therapeutic strategy for atherogenesis.