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Why is the expression of \u03b22GPI observed in the placenta despite its abundance in the circulating blood of healthy individuals? Does the placenta produce a specific-acting \u03b22GPI?. \u03b22GPI was recently shown to adopt two interconvertible biochemical confirmations based on the integrity of disulfide bonds: oxidized and reduced. The present study investigates the physiological function of \u03b22GPI in trophoblast cells, with a focus on the reduced and oxidized forms of \u03b22GPI under the hypothesis that placental \u03b22GPI has a different activity from circulating \u03b22GPI. Endogenous \u03b22GPI secretion in trophoblast cells were predominantly in the reduced form, while those in HepG2 liver cells were mainly in the oxidized form. Progesterone increased reduced-\u03b22GPI in both the trophoblast and liver cells. Oxidized-\u03b22GPI significantly inhibited trophoblast cell migration and increased placental soluble fms-like tyrosine kinase-1 (sFlt-1). Furthermore, excess sFlt-1 significantly increased oxidized-\u03b22GPI secretion in HepG2 cells. Circulating oxidized-\u03b22GPI levels were significantly higher in women with pre-eclampsia than in those without pre-eclampsia. Therefore, oxidized-\u03b22GPI may contribute to the pathogenesis of pre-eclampsia. Under oxidative stress, the excessive oxidation of \u03b22GPI and\/or excessive placental sFlt-1 may trigger a negative spiral between trophoblast and liver cells.<\/jats:p>","DOI":"10.1371\/journal.pone.0321405","type":"journal-article","created":{"date-parts":[[2025,4,25]],"date-time":"2025-04-25T17:21:52Z","timestamp":1745601712000},"page":"e0321405","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":3,"title":["Beyond antibodies: Beta-2 glycoprotein I as the unsung guardian of pregnancy"],"prefix":"10.1371","volume":"20","author":[{"given":"Kazunobu","family":"Yagi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reina","family":"Komatsu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1439-0375","authenticated-orcid":true,"given":"Hitomi","family":"Nakamura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0950-7110","authenticated-orcid":true,"given":"Kazuya","family":"Mimura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masayuki","family":"Endo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takuji","family":"Tomimatsu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tadashi","family":"Kimura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,4,25]]},"reference":[{"key":"pone.0321405.ref001","doi-asserted-by":"crossref","first-page":"17103","DOI":"10.1038\/nrdp.2017.103","article-title":"Antiphospholipid syndrome","volume":"4","author":"K Schreiber","year":"2018","journal-title":"Nat Rev Dis Primers"},{"key":"pone.0321405.ref002","volume-title":"Clinical immunology: principles and practice. 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Structural heterogeneity of apolipoprotein H (beta 2-glycoprotein I)","volume":"42","author":"MI Kamboh","year":"1988","journal-title":"Am J Hum Genet"},{"issue":"10","key":"pone.0321405.ref012","first-page":"420","article-title":"Synthesis of plasma beta 2 glycoprotein I by human hepatoma cells in tissue culture","volume":"21","author":"M Rioche","year":"1974","journal-title":"Biomedicine"},{"issue":"2","key":"pone.0321405.ref013","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1191\/0961203306lu2270oa","article-title":"Circulating levels of beta2-glycoprotein I in thrombotic disorders and in inflammation","volume":"15","author":"F Lin","year":"2006","journal-title":"Lupus"},{"issue":"1","key":"pone.0321405.ref014","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/j.atherosclerosis.2009.09.072","article-title":"APOH is increased in the plasma and liver of type 2 diabetic patients with metabolic syndrome","volume":"209","author":"A Castro","year":"2010","journal-title":"Atherosclerosis"},{"issue":"9","key":"pone.0321405.ref015","first-page":"1684","article-title":"Beta 2 glycoprotein I and placental anticoagulant protein I in placentae from patients with antiphospholipid syndrome","volume":"21","author":"L La Rosa","year":"1994","journal-title":"J Rheumatol"},{"issue":"18","key":"pone.0321405.ref016","doi-asserted-by":"crossref","first-page":"2835","DOI":"10.1182\/blood-2014-08-593624","article-title":"\u03b22-Glycoprotein I\/HLA class II complexes are novel autoantigens in antiphospholipid syndrome","volume":"125","author":"K Tanimura","year":"2015","journal-title":"Blood"},{"issue":"1\u20132","key":"pone.0321405.ref017","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/S0165-0378(97)00063-6","article-title":"Antiphospholipid antibodies or not? 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anti-cardiolipin antibody cofactor activity","volume":"90","author":"JE Hunt","year":"1993","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"2","key":"pone.0321405.ref024","doi-asserted-by":"crossref","first-page":"653","DOI":"10.4049\/jimmunol.152.2.653","article-title":"The fifth domain of beta 2-glycoprotein I contains a phospholipid binding site (Cys281-Cys288) and a region recognized by anticardiolipin antibodies","volume":"152","author":"J Hunt","year":"1994","journal-title":"J Immunol"},{"issue":"24","key":"pone.0321405.ref025","doi-asserted-by":"crossref","first-page":"7429","DOI":"10.1021\/bi0603064","article-title":"Allosteric disulfide bonds","volume":"45","author":"B Schmidt","year":"2006","journal-title":"Biochemistry"},{"issue":"11","key":"pone.0321405.ref026","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1056\/NEJMra1112830","article-title":"The pathogenesis of the antiphospholipid syndrome","volume":"368","author":"B Giannakopoulos","year":"2013","journal-title":"N Engl J Med"},{"issue":"31","key":"pone.0321405.ref027","doi-asserted-by":"crossref","first-page":"10794","DOI":"10.1074\/jbc.RA120.013939","article-title":"The J-elongated conformation of \u03b22-glycoprotein I predominates in solution: implications for our understanding of antiphospholipid syndrome","volume":"295","author":"E Ruben","year":"2020","journal-title":"J Biol Chem"},{"key":"pone.0321405.ref028","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1007\/978-1-4939-9187-7_17","article-title":"Quantitation of Total and Free Thiol \u03b22-Glycoprotein I Levels for Diagnostic and Prognostic Purposes in the Antiphospholipid Syndrome","volume":"1967","author":"M Qi","year":"2019","journal-title":"Methods Mol Biol"},{"issue":"11","key":"pone.0321405.ref029","doi-asserted-by":"crossref","first-page":"2794","DOI":"10.1161\/ATVBAHA.120.315156","article-title":"Free Thiol \u03b22-GPI (\u03b2-2-Glycoprotein-I) Provides a Link Between 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Raimondo","year":"2017","journal-title":"PLoS One"},{"issue":"5","key":"pone.0321405.ref038","doi-asserted-by":"crossref","first-page":"481.e1-7","DOI":"10.1016\/j.ajog.2008.07.048","article-title":"Diagnosis and management of atypical preeclampsia-eclampsia","volume":"200","author":"BM Sibai","year":"2009","journal-title":"Am J Obstet Gynecol"},{"issue":"12","key":"pone.0321405.ref039","doi-asserted-by":"crossref","first-page":"2553","DOI":"10.1182\/blood-2008-12-190629","article-title":"Nicked {beta}2-glycoprotein I binds angiostatin 4.5 (plasminogen kringle 1-5) and attenuates its antiangiogenic property","volume":"114","author":"H Nakagawa","year":"2009","journal-title":"Blood"},{"issue":"3","key":"pone.0321405.ref040","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1016\/j.jaut.2010.06.013","article-title":"In vivo modulation of angiogenesis by beta 2 glycoprotein I","volume":"35","author":"FH Passam","year":"2010","journal-title":"J Autoimmun"},{"issue":"2","key":"pone.0321405.ref041","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.canlet.2010.04.010","article-title":"Plasmin-clipped beta(2)-glycoprotein-I inhibits endothelial cell growth by down-regulating cyclin A, B and D1 and up-regulating p21 and p27","volume":"296","author":"W-DC Beecken","year":"2010","journal-title":"Cancer Lett"},{"key":"pone.0321405.ref042","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.canlet.2020.08.039","article-title":"Beta2 glycoprotein I-derived therapeutic peptides induce sFlt-1 secretion to reduce melanoma vascularity and growth","volume":"495","author":"H Smalley","year":"2020","journal-title":"Cancer Lett"},{"issue":"2S","key":"pone.0321405.ref043","doi-asserted-by":"crossref","first-page":"S1019","DOI":"10.1016\/j.ajog.2020.10.022","article-title":"Imbalances in circulating angiogenic factors in the pathophysiology of preeclampsia and related disorders","volume":"226","author":"S Rana","year":"2022","journal-title":"Am J Obstet Gynecol"},{"issue":"11","key":"pone.0321405.ref044","doi-asserted-by":"crossref","first-page":"4838","DOI":"10.1210\/en.2004-0533","article-title":"Cytotrophoblasts up-regulate soluble fms-like tyrosine kinase-1 expression under reduced oxygen: an implication for the placental vascular development and the pathophysiology of preeclampsia","volume":"145","author":"T Nagamatsu","year":"2004","journal-title":"Endocrinology"},{"issue":"12","key":"pone.0321405.ref045","first-page":"3954","article-title":"Uterine DCs are crucial for decidua formation during embryo implantation in mice","volume":"118","author":"V Plaks","year":"2008","journal-title":"J Clin Invest"},{"issue":"8","key":"pone.0321405.ref046","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1016\/0002-9378(83)90243-0","article-title":"Endocrinologic events in early pregnancy failure","volume":"147","author":"MO Aspillaga","year":"1983","journal-title":"Am J Obstet Gynecol"},{"issue":"5","key":"pone.0321405.ref047","first-page":"1122","article-title":"Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists\u2019 Task Force on Hypertension in Pregnancy","volume":"122","year":"2013","journal-title":"Obstet Gynecol"},{"issue":"5","key":"pone.0321405.ref048","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1038\/s41581-019-0119-6","article-title":"Pre-eclampsia: pathogenesis, novel diagnostics and therapies","volume":"15","author":"EA Phipps","year":"2019","journal-title":"Nat Rev Nephrol"},{"issue":"5","key":"pone.0321405.ref049","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1172\/JCI17189","article-title":"Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia","volume":"111","author":"SE Maynard","year":"2003","journal-title":"J Clin Invest"},{"issue":"1","key":"pone.0321405.ref050","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.semnephrol.2010.10.004","article-title":"Angiogenic factors and 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