Biomaterial Database

Protein disulfide isomerase-A1 regulates intraplatelet reactive oxygen species-thromboxane A2 -dependent pathway in human platelets. 2022

Kamil Przyborowski, and Anna Kurpinska, and Dagmara Wojkowska, and Patrycja Kaczara, and Joanna Suraj-Prazmowska, and Kamil Karolczak, and Agata Malinowska, and Agnieszka Pelesz, and Agnieszka Kij, and Ivars Kalvins, and Cezary Watala, and Stefan Chlopicki

Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Krakow, Poland.

Platelet-derived protein disulfide isomerase 1 (PDIA1) regulates thrombus formation, but its role in the regulation of platelet function is not fully understood. The aim of this study was to characterize the role of PDIA1 in human platelets. Proteomic analysis of PDI isoforms in platelets was performed using liquid chromatography tandem mass spectometry, and the expression of PDIs on platelets in response to collagen, TRAP-14, or ADP was measured with flow cytometry. The effects of bepristat, a selective PDIA1 inhibitor, on platelet aggregation, expression of platelet surface activation markers, thromboxane A2 (TxA2 ), and reactive oxygen species (ROS) generation were evaluated by optical aggregometry, flow cytometry, ELISA, and dihydrodichlorofluorescein diacetate-based fluorescent assay, respectively. PDIA1 was less abundant compared with PDIA3 in resting platelets and platelets stimulated with TRAP-14, collagen, or ADP. Collagen, but not ADP, induced a significant increase in PDIA1 expression. Bepristat potently inhibited the aggregation of washed platelets induced by collagen or convulxin, but only weakly inhibited platelet aggregation induced by TRAP-14 or thrombin, and had the negligible effect on platelet aggregation induced by arachidonic acid. Inhibition of PDIA1 by bepristat resulted in the reduction of TxA2 and ROS production in collagen- or thrombin-stimulated platelets. Furthermore, bepristat reduced the activation of αIIbβ3 integrin and expression of P-selectin. PDIA1 acts as an intraplatelet regulator of the ROS-TxA2 pathway in collagen-GP VI receptor-mediated platelet activation that is a mechanistically distinct pathway from extracellular regulation of αIIbβ3 integrin by PDIA3.

UI	MeSH Term	Description	Entries
D010974	Platelet Aggregation	The attachment of PLATELETS to one another. This clumping together can be induced by a number of agents (e.g., THROMBIN; COLLAGEN) and is part of the mechanism leading to the formation of a THROMBUS.	Aggregation, Platelet
D001792	Blood Platelets	Non-nucleated disk-shaped cells formed in the megakaryocyte and found in the blood of all mammals. They are mainly involved in blood coagulation.	Platelets,Thrombocytes,Blood Platelet,Platelet,Platelet, Blood,Platelets, Blood,Thrombocyte
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D013928	Thromboxane A2	An unstable intermediate between the prostaglandin endoperoxides and thromboxane B2. The compound has a bicyclic oxaneoxetane structure. It is a potent inducer of platelet aggregation and causes vasoconstriction. It is the principal component of rabbit aorta contracting substance (RCS).	Rabbit Aorta Contracting Substance,A2, Thromboxane
D013931	Thromboxanes	Physiologically active compounds found in many organs of the body. They are formed in vivo from the prostaglandin endoperoxides and cause platelet aggregation, contraction of arteries, and other biological effects. Thromboxanes are important mediators of the actions of polyunsaturated fatty acids transformed by cyclooxygenase.	Thromboxane
D017382	Reactive Oxygen Species	Molecules or ions formed by the incomplete one-electron reduction of oxygen. These reactive oxygen intermediates include SINGLET OXYGEN; SUPEROXIDES; PEROXIDES; HYDROXYL RADICAL; and HYPOCHLOROUS ACID. They contribute to the microbicidal activity of PHAGOCYTES, regulation of SIGNAL TRANSDUCTION and GENE EXPRESSION, and the oxidative damage to NUCLEIC ACIDS; PROTEINS; and LIPIDS.	Active Oxygen Species,Oxygen Radical,Oxygen Radicals,Pro-Oxidant,Reactive Oxygen Intermediates,Active Oxygen,Oxygen Species, Reactive,Pro-Oxidants,Oxygen, Active,Pro Oxidant,Pro Oxidants,Radical, Oxygen
D019704	Protein Disulfide-Isomerases	Sulfur-sulfur bond isomerases that catalyze the rearrangement of disulfide bonds within proteins during folding. Specific protein disulfide-isomerase isoenzymes also occur as subunits of PROCOLLAGEN-PROLINE DIOXYGENASE.	Protein Disulfide Isomerase,Protein Disulfide-Isomerase,Disulfide Interchange Enzyme,Disulfide Isomerase,Glycosylation Site-Binding Protein,Sulfhydryl-Disulfide Interchange Enzyme,Thiol-Disulfide Transhydrogenase,Trypanothione-Glutathione Thioltransferase,Disulfide Isomerase, Protein,Disulfide-Isomerase, Protein,Disulfide-Isomerases, Protein,Enzyme, Disulfide Interchange,Enzyme, Sulfhydryl-Disulfide Interchange,Glycosylation Site Binding Protein,Interchange Enzyme, Disulfide,Interchange Enzyme, Sulfhydryl-Disulfide,Isomerase, Disulfide,Isomerase, Protein Disulfide,Protein Disulfide Isomerases,Protein, Glycosylation Site-Binding,Site-Binding Protein, Glycosylation,Sulfhydryl Disulfide Interchange Enzyme,Thiol Disulfide Transhydrogenase,Thioltransferase, Trypanothione-Glutathione,Transhydrogenase, Thiol-Disulfide,Trypanothione Glutathione Thioltransferase
D040901	Proteomics	The systematic study of the complete complement of proteins (PROTEOME) of organisms.	Peptidomics