{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T10:22:13Z","timestamp":1788344533116,"version":"build-2803163510"},"reference-count":52,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"10","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2019,3,5]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>Platelet-neutrophil interactions contribute to vascular occlusion and tissue damage in thromboinflammatory disease. Platelet glycoprotein Ib\u03b1 (GPIb\u03b1), a key receptor for the cell-cell interaction, is believed to be constitutively active for ligand binding. Here, we established the role of platelet-derived protein disulfide isomerase (PDI) in reducing the allosteric disulfide bonds in GPIb\u03b1 and enhancing the ligand-binding activity under thromboinflammatory conditions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>Bioinformatic analysis identified 2 potential allosteric disulfide bonds in GPIb\u03b1. Agglutination assays, flow cytometry, surface plasmon resonance analysis, a protein-protein docking model, proximity ligation assays, and mass spectrometry were used to demonstrate a direct interaction between PDI and GPIb\u03b1 and to determine a role for PDI in regulating GPIb\u03b1 function and platelet-neutrophil interactions. Also, real-time microscopy and animal disease models were used to study the pathophysiological role of PDI-GPIb\u03b1 signaling under thromboinflammatory conditions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>Deletion or inhibition of platelet PDI significantly reduced GPIb\u03b1-mediated platelet agglutination. Studies using PDI-null platelets and recombinant PDI or Anfibatide, a clinical-stage GPIb\u03b1 inhibitor, revealed that the oxidoreductase activity of platelet surface\u2013bound PDI was required for the ligand-binding function of GPIb\u03b1. PDI directly bound to the extracellular domain of GPIb\u03b1 on the platelet surface and reduced the Cys4-Cys17 and Cys209-Cys248 disulfide bonds. Real-time microscopy with platelet-specific PDI conditional knockout and sickle cell disease mice demonstrated that PDI-regulated GPIb\u03b1 function was essential for platelet-neutrophil interactions and vascular occlusion under thromboinflammatory conditions. Studies using a mouse model of ischemia\/reperfusion\u2013induced stroke indicated that PDI-GPIb\u03b1 signaling played a crucial role in tissue damage.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>Our results demonstrate that PDI-facilitated cleavage of the allosteric disulfide bonds tightly regulates GPIb\u03b1 function, promoting platelet-neutrophil interactions, vascular occlusion, and tissue damage under thromboinflammatory conditions.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.118.036323","type":"journal-article","created":{"date-parts":[[2019,1,9]],"date-time":"2019-01-09T16:19:56Z","timestamp":1547050796000},"page":"1300-1319","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":96,"title":["Platelet Protein Disulfide Isomerase Promotes Glycoprotein Ib\u03b1\u2013Mediated Platelet-Neutrophil Interactions Under Thromboinflammatory Conditions"],"prefix":"10.1161","volume":"139","author":[{"given":"Jing","family":"Li","sequence":"first","affiliation":[{"name":"Department of Pharmacology, University of Illinois College of Medicine, Chicago (J.L., K.K., S.-Y.J, B.X., X. Du, J. Cho)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyungho","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Illinois College of Medicine, Chicago (J.L., K.K., S.-Y.J, B.X., X. Du, J. Cho)."},{"name":"Korean Medicine-Application Center, Korea Institute of Oriental Medicine, Daegu (K.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Si-Yeon","family":"Jeong","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Illinois College of Medicine, Chicago (J.L., K.K., S.-Y.J, B.X., X. Du, J. Cho)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joyce","family":"Chiu","sequence":"additional","affiliation":[{"name":"The Centenary Institute, Newtown, NSW, Australia (J. Chiu, P.J.H.)."},{"name":"National Health and Medical Research Council Clinical Trials Centre, University of Sydney, NSW, Australia (J. Chiu, P.J.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bei","family":"Xiong","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Illinois College of Medicine, Chicago (J.L., K.K., S.-Y.J, B.X., X. Du, J. Cho)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pavel A.","family":"Petukhov","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry and Pharmacognosy, University of Illinois College of Pharmacy, Chicago (P.A.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangrong","family":"Dai","sequence":"additional","affiliation":[{"name":"Lee\u2019s Pharmaceutical Holdings Ltd, Shatin, Hong Kong (X. Dai, X.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyi","family":"Li","sequence":"additional","affiliation":[{"name":"Lee\u2019s Pharmaceutical Holdings Ltd, Shatin, Hong Kong (X. Dai, X.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert K.","family":"Andrews","sequence":"additional","affiliation":[{"name":"Australian Centre for Blood Diseases, Monash University, Melbourne, VIC (R.K.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoping","family":"Du","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Illinois College of Medicine, Chicago (J.L., K.K., S.-Y.J, B.X., X. Du, J. Cho)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip J.","family":"Hogg","sequence":"additional","affiliation":[{"name":"The Centenary Institute, Newtown, NSW, Australia (J. Chiu, P.J.H.)."},{"name":"National Health and Medical Research Council Clinical Trials Centre, University of Sydney, NSW, Australia (J. 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