Thiol Isomerases in Thrombus Formation

Abstract

Protein disulfide isomerase, ERp5 and ERp57, among perhaps other thiol isomerases, are important for the initiation of thrombus formation. Using the laser injury thrombosis model in mice to induce in vivo arterial thrombus formation, it was shown that thrombus formation is associated with PDI secretion by platelets, that inhibition of PDI blocked platelet thrombus formation and fibrin generation, and that endothelial cell activation leads to PDI secretion. Similar results using this and other thrombosis models in mice have demonstrated the importance of ERp5 and ERp57 in the initiation of thrombus formation. The integrins αIIbβ3 and αVβ3 play a key role in this process and interact directly with PDI, ERp5 and ERp57. The mechanism by which thiol isomerases participate in thrombus generation is being evaluated using trapping mutant forms to identify substrates of thiol isomerases that participate in the network pathways linking thiol isomerases, platelet receptor activation and fibrin generation. Protein disulfide isomerase as an antithrombotic target is being explored using isoquercetin and quercetin 3-rutinoside, inhibitors of PDI identified by high throughput screening. Regulation of thiol isomerase expression, analysis of the storage and secretion of thiol isomerases and determination of the electron transfer pathway are key issues to understanding this newly discovered mechanism of regulation of the initiation of thrombus formation.

Peri/Epicellular Protein Disulfide Isomerase Sustains Vascular Lumen Caliber Through an Anticonstrictive Remodeling Effect

“…29 Our data add to other specific effects of pecPDI pool, which include immune reactions, 16 pathogen response, 16,27 and thrombosis. [18][19][20][21] Subcellular routes of PDI externalization remain elusive. 12 Endothelial PDI externalization is an early response-to-injury signal, 19 supporting integrin-mediated platelet accumulation, fibrin formation, 30 and neutrophil recruitment.…”

“…18,21,26 Thiol reductants generally mediate integrin activation. 13,21,27 We addressed whether β1-integrin is a pecPDI target in our model. In injured arteries, pecPDI neutralization decreased extracellular thiol levels ( Figure 6A).…”

“…18 Importantly, pecPDI sustains injury-associated thrombosis, 19 and inhibitors of PDI family proteins are among the most innovative antithrombotic strategies. 20,21 Moreover, pecPDI exerts predominant thiol reductase activity 12,13,18 and mediates transnitrosation reactions that govern nitric oxide bioavailability. 12 Given the redox sensitivity of vessel remodeling, the involvement of PDI in redox signaling and homeostasis and, in particular, the characteristics of pecPDI discussed above, we hypothesized that the pecPDI pool regulates vascular remodeling.…”

Protein disulfide isomerase inhibition blocks thrombin generation in humans by interfering with platelet factor V activation

“…Within the vasculature, platelets and endothelial cells secrete PDI in the context of vascular injury or inflammation. Several animal models have demonstrated that extracellular PDI has a critical role in thrombus formation (1,2). Inhibition of PDI by either monoclonal antibodies or small-molecule inhibitors prevents both platelet accumulation and fibrin formation at sites of vessel injury (2)(3)(4).…”

Thiol Isomerases – A Possible Target for Thrombosis Control

“…Похожие результаты были получены также и для ERp57 и ERp5 (подробную информацию можно полу-чить из обзоров [16,17]). …”