3, 5, 2′, 4′-Tetramethoxystilbene, a fully methylated resveratrol analog, prevents platelet aggregation and thrombus formation by targeting the protease-activated receptor 4 pathway. (25th April 2022)

• Record Type: Journal Article
• Authors: Chiang, Yi-Chun; Wu, Yu-Shan; Kang, Ya-Fei; Wang, Hui-Chun; Tsai, Meng-Chun; Wu, Chin-Chung
• Is Part Of: Chemico-biological interactions. Volume 357(2022)
• Publication Date: 2022-04-25
• Subjects: Antiplatelet agents -- Platelets -- Protease-activated receptors -- Resveratrol -- 3, 5, 2′, 4′-tetramethoxystilbene; Biochemistry -- Periodicals; Toxicological chemistry -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biochimie -- Périodiques; Toxicologie biochimique -- Périodiques; 572
• DOI: 10.1016/j.cbi.2022.109889
• Languages: English
• ISSNs: 0009-2797

Abstract

Abstract: Thrombin is a potent platelet activator and a key mediator of blood coagulation, thereby playing a crucial role in cardiovascular disease. Recently, protease-activated receptor 4 (PAR4), one of thrombin receptors in human platelets, is emerging as a promising target for antiplatelet therapy. 3, 5, 2′, 4′-Tetramethoxystilbene (TMS), a resveratrol analog, have demonstrated promising effects on preventing atherosclerosis and hypertension, whereas its antiplatelet effect has never been investigated. Herein we show that TMS at concentrations of a few micromolar selectively inhibits PAR4-mediated human platelet aggregation, ATP secretion, integrin αIIbβ3 activation, and signaling pathways. In a whole-blood model of arterial flow, TMS also significantly reduced in vitro thrombus formation. Analysis of the structure-activity relationships of TMS and a panel of stilbene analogs reveal that full methylation of hydroxy groups of the stilbenes is the critical structural determinant for the anti-PAR4 activity. Our results suggest that fully methylated resveratrol analogs with anti-PAR4 activity are potential candidates for development of novel antiplatelet agents. Graphical abstract: Image 1 Highlights: The resveratrol derivative, TMS, shows selective inhibition of PAR4-mediated human platelet aggregation. TMS reduced in vitro thrombus formation under whole blood flow conditions. Methylation of the hydroxy groups of the resveratrol derivatives is critical for the anti-PAR4 activity.