Deletion of Zyxin Reduces Endothelial Inflammation and Mitigates Atherosclerosis

Abstract

BACKGROUNDOscillatory shear stress (OSS)-induced endothelial inflammation plays a critical role in the pathogenesis of atherosclerosis. However, the involvement of endothelial zyxin, a mechanosensor, in OSS-associated atherosclerosis and its underlying mechanisms remains unclear. METHODSTo investigate the role of zyxin in vivo, ZyxiniECKOApoE-/- mice were utilized in atherosclerosis model induced by carotid artery ligation; in vitro, endothelial cells were subjected to disturbed flow in Ibidi systerm. RESULTSZyxin was significantly upregulated in the OSS regions of both human and mouse arteries. The specific deletion of zyxin in endothelial cells (ECs) in ApoE-/- (ZyxiniECKOApoE-/-) mice reversed the ECs activation and atherosclerosis induced by OSS. In vitro studies indicated that the absence of zyxin reduced the induction of adhesion molecules and pro-inflammatory cytokines stimulated by OSS. Mechanistic investigations demonstrated that 14-3-3{beta} facilitated yes-associated protein (YAP) phosphorylation at Serine 127, which played a critical role in retaining YAP within the cytoplasm. Under OSS stimulation, zyxin inhibited the phosphorylation of YAP at Serine 127 through its interaction with 14-3-3{beta}, rather than direct regulation of YAP. This inhibition enhanced YAPs nuclear translocation and promoted endothelial inflammation. Furthermore, it was shown that rosuvastatin inhibited zyxin expression in human umbilical vein endothelial cells and the vascular endothelium of ApoE-/- mice. This inhibition led to decreased levels of inflammatory markers and adhesion molecules associated with atherosclerotic lesions observed in the partially ligated left common carotid arteries of ApoE-/- mice. CONCLUSIONSThis study further confirms that zyxin is a mechanoreceptor in endothelial cells and elucidates the indispensable role of the zyxin-14-3-3{beta}-YAP axis in endothelial inflammation and atherogenesis. This indicates that Zyxin plays a crucial role in protecting against atherosclerosis.