title: Inhibition of Protein Disulfide Isomerase in Thrombosis.
abstract: This MiniReview addresses our current understanding of the mechanisms by which protein disulfide isomerase (PDI) mediates thrombus formation and discusses the potential of blocking thrombosis by targeting PDI. Thiol isomerases are ubiquitous oxidoreductases primarily localized to the endoplasmic reticulum (ER) where they serve a critical role in protein folding. PDI is the founding member of the thiol isomerase family. Although PDI is an essential intracellular enzyme, it can participate in pathological processes once released from cells. In particular, PDI serves a critical role in thrombus formation, the underlying cause of myocardial infarction and stroke. Both platelets and endothelial cells secrete PDI upon vascular injury. Secreted PDI appears to activate multiple extracellular substrates in the vasculature, enabling the initiation of thrombus formation. As an essential component of thrombus formation, extracellular PDI represents a new target for pharmacological inhibition of clinical thrombosis. Quercetin-3-rutinoside, a flavonol highly abundant in common foods, inhibits PDI and blocks thrombus formation both in vitro and in vivo. Such observations have prompted clinical trials targeting PDI in thrombotic diseases.
authors.affiliation: Division of Hemostasis and Thrombosis, Department of Medicine, BIDMC, Harvard Medical School, Boston, MA, USA.
authors.forename: Roelof H
authors.initials: RH
authors.lastname: Bekendam
authors.affiliation: Division of Hemostasis and Thrombosis, Department of Medicine, BIDMC, Harvard Medical School, Boston, MA, USA. rflaumen@bidmc.harvard.edu.
authors.forename: Robert
authors.initials: R
authors.lastname: Flaumenhaft
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000627:therapeutic use*; D055162:Biocatalysis; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006801:Humans; D009203:Myocardial Infarction / Q000209:etiology / Q000517:prevention & control; D019704:Protein Disulfide-Isomerases / Q000037:antagonists & inhibitors* / Q000097:blood / Q000378:metabolism; D017510:Protein Folding / Q000187:drug effects; D012431:Rutin / Q000627:therapeutic use; D020521:Stroke / Q000209:etiology / Q000517:prevention & control; D013379:Substrate Specificity; D013927:Thrombosis / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology
chemical_list: D000925:Anticoagulants; D004791:Enzyme Inhibitors; D012431:Rutin; D019704:Protein Disulfide-Isomerases