Guan Ivy A, Liu Joanna S T, Sawyer Renata C, Li Xiang, Jiao Wanting, Jiramongkol Yannasittha, White Mark D, Hagimola Lejla, Passam Freda H, Tran Denise P, Liu Xiaoming, Schoenwaelder Simone M, Jackson Shaun P, Payne Richard J, Liu Xuyu
School of Chemistry, Faculty of Science, The University of Sydney, Sydney, New South Wales 2006, Australia.
The Heart Research Institute, The University of Sydney, Newtown, New South Wales 2042, Australia.
ACS Cent Sci. 2024 Jan 29;10(2):344-357. doi: 10.1021/acscentsci.3c00822. eCollection 2024 Feb 28.
A large variety of dietary phytochemicals has been shown to improve thrombosis and stroke outcomes in preclinical studies. Many of these compounds feature electrophilic functionalities that potentially undergo covalent addition to the sulfhydryl side chain of cysteine residues within proteins. However, the impact of such covalent modifications on the platelet activity and function remains unclear. This study explores the irreversible engagement of 23 electrophilic phytochemicals with platelets, unveiling the unique antiplatelet selectivity of sulforaphane (SFN). SFN impairs platelet responses to adenosine diphosphate (ADP) and a thromboxane A2 receptor agonist while not affecting thrombin and collagen-related peptide activation. It also substantially reduces platelet thrombus formation under arterial flow conditions. Using an alkyne-integrated probe, protein disulfide isomerase A6 (PDIA6) was identified as a rapid kinetic responder to SFN. Mechanistic profiling studies revealed SFN's nuanced modulation of PDIA6 activity and substrate specificity. In an electrolytic injury model of thrombosis, SFN enhanced the thrombolytic activity of recombinant tissue plasminogen activator (rtPA) without increasing blood loss. Our results serve as a catalyst for further investigations into the preventive and therapeutic mechanisms of dietary antiplatelets, aiming to enhance the clot-busting power of rtPA, currently the only approved therapeutic for stroke recanalization that has significant limitations.
在临床前研究中，已证明多种膳食植物化学物质可改善血栓形成和中风预后。这些化合物中的许多都具有亲电功能基团，可能会与蛋白质中半胱氨酸残基的巯基侧链发生共价加成。然而，这种共价修饰对血小板活性和功能的影响仍不清楚。本研究探讨了23种亲电植物化学物质与血小板的不可逆结合，揭示了萝卜硫素（SFN）独特的抗血小板选择性。SFN会损害血小板对二磷酸腺苷（ADP）和血栓素A2受体激动剂的反应，而不影响凝血酶和胶原相关肽的激活。它还能在动脉血流条件下显著减少血小板血栓形成。使用炔烃整合探针，蛋白质二硫键异构酶A6（PDIA6）被确定为对SFN有快速动力学反应的蛋白。机制分析研究揭示了SFN对PDIA6活性和底物特异性的细微调节。在血栓形成的电解损伤模型中，SFN增强了重组组织型纤溶酶原激活剂（rtPA）的溶栓活性，而不增加失血量。我们的研究结果为进一步研究膳食抗血小板药物的预防和治疗机制提供了契机，旨在增强rtPA的溶栓能力，rtPA是目前唯一被批准用于中风再通治疗的药物，但存在显著局限性。
