c-Abl regulates [YAP.sup.Y357] phosphorylation to activate endothelial atherogenic responses to disturbed flow

Introduction Atherosclerosis has become one of the major causes of death worldwide because of its severe complications, such as acute myocardial infarction and stroke (1). Vascular endothelial cell (EC) activation [...]
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~h 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.sup.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.sup.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.sup.Y357] and the development of atherosclerosis in [Apoe.sup.-/-] mice. The c-Abl/[YAP.sup.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.