Vinculin phosphorylation impairs vascular endothelial junctions promoting atherosclerosis

Yu Tsung Shih, Shu Yi Wei, Jin Hua Chen, Wei Li Wang, Hsin Yi Wu, Mei Cun Wang, Chia Yu Lin, Pei Lin Lee, Chih Yuan Lin, Hung Che Chiang, Yu Ju Chen, Shu Chien, Jeng Jiann Chiu

研究成果: 雜誌貢獻文章同行評審

3 引文 斯高帕斯(Scopus)


Background and Atherosclerosis preferentially develops in arterial branches and curvatures where vascular endothelium is exposed to dis-aims turbed flow. In this study, the effects of disturbed flow on the regulation of vascular endothelial phosphoproteins and their contribution to therapeutic application in atherogenesis were elucidated. Methods Porcine models, large-scale phosphoproteomics, transgenic mice, and clinical specimens were used to discover novel site-specific phosphorylation alterations induced by disturbed flow in endothelial cells (ECs). Results A large-scale phosphoproteomics analysis of native endothelium from disturbed (athero-susceptible) vs. pulsatile flow (athero-resistant) regions of porcine aortas led to the identification of a novel atherosclerosis-related phosphoprotein vinculin (VCL) with disturbed flow-induced phosphorylation at serine 721 (VCLS721p). The induction of VCLS721p was mediated by G-protein-coupled receptor kinase 2 (GRK2)S29p and resulted in an inactive form of VCL with a closed conformation, leading to the VE-cadherin/catenin complex disruption to enhance endothelial permeability and atherogenesis. The generation of novel apolipoprotein E-deficient (ApoE−/−) mice overexpressing S721-non-phosphorylatable VCL mutant in ECs confirmed the critical role of VCLS721p in promoting atherosclerosis. The administration of a GRK2 inhibitor to ApoE−/− mice suppressed plaque formation by inhibiting endothelial VCLS721p. Studies on clinical specimens from patients with coronary artery disease (CAD) revealed that endothelial VCLS721p is a critical clinicopathological biomarker for atherosclerosis progression and that serum VCLS721p level is a promising biomarker for CAD diagnosis. Conclusions The findings of this study indicate that endothelial VCLS721p is a valuable hemodynamic-based target for clinical assessment and treatment of vascular disorders resulting from atherosclerosis.
頁(從 - 到)304-318
期刊European Heart Journal
出版狀態已發佈 - 1月 2023

ASJC Scopus subject areas

  • 心臟病學與心血管醫學


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