Department of Physiology, University of Toronto, Toronto, ON M5S, Canada.
Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Canada.
Cardiovasc Hematol Disord Drug Targets. 2020;20(4):260-273. doi: 10.2174/1871529X20666201001144541.
Platelets are small blood cells known primarily for their ability to adhere and aggregate at injured vessels to arrest bleeding. However, when triggered under pathological conditions, the same adaptive mechanism of platelet adhesion and aggregation may cause thrombosis, a primary cause of heart attack and stroke. Over recent decades, research has made considerable progress in uncovering the intricate and dynamic interactions that regulate these processes. Integrins are heterodimeric cell surface receptors expressed on all metazoan cells that facilitate cell adhesion, movement, and signaling, to drive biological and pathological processes such as thrombosis and hemostasis. Recently, our group discovered that the plexin-semaphorin-integrin (PSI) domains of the integrin β subunits exert endogenous thiol isomerase activity derived from their two highly conserved CXXC active site motifs. Given the importance of redox reactions in integrin activation and its location in the knee region, this PSI domain activity may be critically involved in facilitating the interconversions between integrin conformations. Our monoclonal antibodies against the β3 PSI domain inhibited its thiol isomerase activity and proportionally attenuated fibrinogen binding and platelet aggregation. Notably, these antibodies inhibited thrombosis without significantly impairing hemostasis or causing platelet clearance. In this review, we will update mechanisms of thrombosis and hemostasis, including platelet versatilities and immune-mediated thrombocytopenia, discuss critical contributions of the newly discovered PSI domain thiol isomerase activity, and its potential as a novel target for anti-thrombotic therapies and beyond.
血小板是一种小的血细胞，主要因其在受伤血管处黏附和聚集以止血的能力而闻名。然而，当在病理条件下被触发时，血小板黏附和聚集的相同适应性机制可能导致血栓形成，这是心脏病发作和中风的主要原因。近几十年来，研究在揭示调节这些过程的复杂和动态相互作用方面取得了相当大的进展。整合素是在所有后生动物细胞上表达的异二聚体细胞表面受体，它促进细胞黏附、运动和信号转导，从而驱动血栓形成和止血等生物学和病理过程。最近，我们小组发现整合素β亚基的丛集蛋白-神经递质-整合素（PSI）结构域具有源自其两个高度保守的CXXC 活性位点基序的内源性硫醇异构酶活性。鉴于氧化还原反应在整合素激活中的重要性及其在膝区的位置，这种 PSI 结构域活性可能在促进整合素构象的相互转换中起着关键作用。我们针对β3 PSI 结构域的单克隆抗体抑制了其硫醇异构酶活性，并相应地减弱了纤维蛋白原结合和血小板聚集。值得注意的是，这些抗体抑制了血栓形成，而没有明显损害止血或导致血小板清除。在这篇综述中，我们将更新血栓形成和止血的机制，包括血小板的多功能性和免疫介导的血小板减少症，讨论新发现的 PSI 结构域硫醇异构酶活性的关键贡献及其作为新型抗血栓治疗靶点的潜力及其他方面。
