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Thiol isomerases orchestrate thrombosis and haemostasis

Simoes Gaspar, R. and Gibbins, J. M. ORCID: https://orcid.org/0000-0002-0372-5352 (2021) Thiol isomerases orchestrate thrombosis and haemostasis. Antioxidants & Redox Signaling. ISSN 1523-0864

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To link to this item DOI: 10.1089/ars.2021.0086

Abstract/Summary

Since protein disulphide isomerase (PDI) was first described in 1963, researchers have shown conclusively that PDI and sibling proteins are quintessential for thrombus formation. PDI, ERp5, ERp57 and ERp72, which in most cells are located in the endoplasmic reticulum and function to assist the folding of nascent protein, are released from platelets and vascular cells and interact with integrin αIIbβ3 on the outer surface of platelets. At the cell surface they continue to influence protein folding and function, propagating thrombosis and maintaining haemostasis. TMX1, which is a transmembrane thiol isomerase, is the first family member shown to negatively regulate platelets known to date. Targets of thiol isomerases have been indentified including integrin α2β1, Von Willebrand Factor (VWF), GpIbα, Nox-1, Nox-2 and tissue factor, all of which are pro-thrombotic, and several of which are on the cell surface. In spite of this, PDI can paradoxically catalyse the delivery of nitric oxide to platelets, which inhibits their function and decreases thrombus formation. Although the overall effect of PDI is to positively regulate platelet activation, it is still unclear how thiol isomerases function in pro-thrombotic states, such as obesity, diabetes and cancer. In parallel, there has been a surge in the development of novel thiol isomerase inhibitors, which display selectivity, potency and modulate thrombosis and haemostasis. The availability of selective thiol isomerase inhibitors has culminated in clinical trials with promising outcomes for the prevention of cancer-associated thrombosis. Altogether, thiol isomerases are perceived as an orchestrating force that regulates thrombus development. In the current review we will explore the history of PDI in cardiovascular biology, detail known mechanisms of action and summarise known thiol isomerase inhibitors.

Item Type:Article
Refereed:Yes
Divisions:Interdisciplinary centres and themes > Institute for Cardiovascular and Metabolic Research (ICMR)
Life Sciences > School of Biological Sciences > Biomedical Sciences
ID Code:97598
Uncontrolled Keywords:Protein disulphide isomerase, platelet, thrombosis, thiol isomerase, history, inhibitors
Publisher:Mary Ann Leibert Inc

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