Journal
BLOOD
Volume 133, Issue 3, Pages 246-251Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2018-04-844480
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Funding
- National Institutes of Health, National Heart, Lung, and Blood Institute [R01 HL118526]
- National Natural Science Foundation of China [81770138, 91539122, 81670133]
- Priority Academic Program Development of Jiangsu Higher Education Institutions
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Secreted platelet protein disulfide isomerases, PDI, ERp57, ERp5, and ERp72, have important roles as positive regulators of platelet function and thrombosis. Thioredoxin-related transmembrane protein 1 (TMX1) was the first described transmembrane member of the protein disulfide isomerase family of enzymes. Using a specific antibody, the recombinant extracellular domain of TMX1 (rTMX1) protein, a knockout mouse model, and a thiol-labeling approach, we examined the role of TMX1 in platelet function and thrombosis. Expression of TMX1 on the platelet surface increased with thrombin stimulation. The anti-TMX1 antibody increased platelet aggregation induced by convulxin and thrombin, as well as potentiated platelet ATP release. In contrast, rTMX1 inhibited platelet aggregation and ATP release. TMX1-deficient platelets had increased aggregation, ATP release, alpha IIb beta 3 activation, and P-selectin expression, which were reversed by addition of rTMX1. TMX1-knockout mice had increased incorporation of platelets into a growing thrombus in an FeCl3-induced mesenteric arterial injury model, as well as shortened tail-bleeding times. rTMX1 oxidized thiols in the alpha IIb beta 3 integrin and TMX1-deficient platelets had increased thiols in the beta 3 subunit of alpha IIb beta 3, consistent with oxidase activity of rTMX1 against alpha IIb beta 3. Thus, TMX1 is the first identified extracellular inhibitor of platelet function and the first disulfide isomerase that negatively regulates platelet function.
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