Recent advances in vascular thiol isomerases and redox systems in platelet function and thrombosis

• DOI: 10.1016/j.jtha.2024.03.008
• Publication Date: 2024-03-20T22:47:28Z
• Authors: David W. Essex; Lu Wang
• Keywords: Blood Platelets; Oxidative Stress; Membrane Glycoproteins; Platelet Aggregation; Protein Disulfide-Isomerases; Humans; Animals; Membrane Proteins; Thrombosis; Platelet Glycoprotein GPIIb-IIIa Complex; Sulfhydryl Compounds; Platelet Activation; Oxidation-Reduction

There have been substantial advances in vascular protein disulfide isomerases (PDIs) in platelet function and thrombosis in recent years. There are 4 known prothrombotic thiol isomerases; PDI, endoplasmic reticulum protein (ERp)57, ERp72, and ERp46, and 1 antithrombotic PDI; transmembrane protein 1. A sixth PDI, ERp5, may exhibit either prothrombotic or antithrombotic 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 transmembrane protein 1 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. 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 of these proteins, although the extent to which the PDIs regulate these functions is unclear. We are beginning to understand the substrates and functions of vascular thiol isomerases and the redox network they form that supports hemostasis and thrombosis. Moreover, the disulfide bonds these enzymes target are being defined. The clinical implications of the knowledge gained are wide-ranging.