Recent Advances in Vascular Thiol Isomerases and Redox Systems in Platelet Function and Thrombosis

J Thromb Haemost. 2024 Mar 20:S1538-7836(24)00166-1. doi: 10.1016/j.jtha.2024.03.008. Online ahead of print.ABSTRACTThere have been substantial advances in vascular protein disulfide isomerases (PDIs) in platelet function and thrombosis in recent years. There are four known prothrombotic thiol isomerases, PDI, ERp57, ERp72, ERp46 and one antithrombotic PDI, transmembrane protein 1 (TMX1). A sixth PDI, ERp5, may exhibit either pro- or anti-thrombotic properties in platelets. Studies on ERp46 in platelet function and thrombosis provide insight into the mechanisms by which these enzymes function. ERp46-catalyzed disulfide cleavage in the αIIbβ3 platelet integrin occurs prior to PDI-catalyzed events to maximally support platelet aggregation. The transmembrane PDI, TMX1, counterbalances the effect of ERp46 by inhibiting activation of αIIbβ3. Recent work on the prototypic PDI found that oxidized PDI supports platelet aggregation. The a¢ domain of PDI is constitutively oxidized, possibly by endoplasmic reticulum oxidoreductase-1α (Ero1α). However, the a domain is normally reduced but becomes oxidized under conditions of oxidative stress. In contrast to the role of oxidized PDI in platelet function, reduced PDI downregulates activation of the neutrophil integrin αMβ2. Intracellular platelet PDI cooperates with Nox1 and contributes to thromboxane A2 production to support platelet function. Finally, αIIb and von Willebrand factor contain free thiols which alter the functions ...
Source: Thrombosis and Haemostasis - Category: Hematology Authors: Source Type: research