Recent Advances in Vascular Thiol Isomerases and Redox Systems in Platelet Funct

There 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 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.