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| 題名: | Vinculin phosphorylation impairs vascular endothelial junctions promoting atherosclerosis. |
| 作者: | 施佑宗
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 |
| 貢獻者: | 醫學系解剖學暨細胞生物學科 |
| 日期: | 2023-01 |
| 上傳時間: | 2025-03-28 13:49:12 (UTC+8) |
| 摘要: | Abstract
Background and aims
Atherosclerosis preferentially develops in arterial branches and curvatures where vascular endothelium is exposed to disturbed 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. |
| 關聯: | European Heart Journal, Volume 44, Issue 4, 21 January 2023, Pages 304–318 |
| 描述: | 【112 新聘】臺北醫學大學教師升等專門著作
職別：專任
送審等級：助理教授
著作送審 |
| 資料類型: | article |
| 顯示於類別: | [教師升等送審著作] 112
[解剖學暨細胞生物學科] 期刊論文
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