title: Defective Association of the Platelet Glycoprotein Ib-IX Complex with the Glycosphingolipid-Enriched Membrane Domain Inhibits Murine Thrombus and Atheroma Formation.
abstract: Localization of the platelet glycoprotein Ib-IX complex to the membrane lipid domain is essential for platelet adhesion to von Willebrand factor and subsequent platelet activation in vitro. Yet, the in vivo importance of this localization has never been addressed. We recently found that the disulfide linkage between Ibα and Ibβ is critical for the association of Ibα with the glycosphingolipid-enriched membrane domain; in this study, we established a transgenic mouse model expressing this mutant human Ibα that is also devoid of endogenous Ibα (HαSSMα(-/-)). Characterization of this model demonstrated a similar dissociation of Ibα from murine platelet glycosphingolipid-enriched membrane to that expressed in Chinese hamster ovary cells, which correlates well with the impaired adhesion of the transgenic platelets to von Willebrand factor ex vivo and in vivo. Furthermore, we bred our transgenic mice into an atherosclerosis-prone background (HαSSMα(-/-)ApoE(-/-) and HαWTMα(-/-)ApoE(-/-)). We observed that atheroma formation was significantly inhibited in mutant mice where fewer platelet-bound CD11c(+) leukocytes were circulating (CD45(+)/CD11c(+)/CD41(+)) and residing in atherosclerotic lesions (CD45(+)/CD11c(+)), suggesting that platelet-mediated adhesion and infiltration of CD11c(+) leukocytes may be one of the mechanisms. To our knowledge, these observations provide the first in vivo evidence showing that the membrane GEM is physiologically and pathophysiologically critical in the function of the glycoprotein Ib-IX complex.
authors.affiliation: Department of Hospital Infection Management of Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Cardiovascular Research Section, Department of Medicine, Baylor College of Medicine, Houston, TX 77030;
authors.forename: Hao
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Cardiovascular Research Section, Department of Medicine, Baylor College of Medicine, Houston, TX 77030;
authors.forename: Yali
authors.identifier: 0000-0003-1871-7264
authors.initials: Y
authors.lastname: Ran
authors.affiliation: Cardiovascular Research Section, Department of Medicine, Baylor College of Medicine, Houston, TX 77030;
authors.forename: Qi
authors.initials: Q
authors.lastname: Da
authors.affiliation: Cardiovascular Research Section, Department of Medicine, Baylor College of Medicine, Houston, TX 77030;
authors.forename: Tanner S
authors.initials: TS
authors.lastname: Shaw
authors.affiliation: Cardiovascular Research Section, Department of Medicine, Baylor College of Medicine, Houston, TX 77030; Department of Vascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China;
authors.forename: Dan
authors.identifier: 0000-0003-4585-2744
authors.initials: D
authors.lastname: Shang
authors.affiliation: Cardiovascular Research Section, Department of Medicine, Baylor College of Medicine, Houston, TX 77030;
authors.forename: Anilkumar K
authors.initials: AK
authors.lastname: Reddy
authors.affiliation: Puget Sound Blood Center, Division of Hematology, Department of Medicine, University of Washington, Seattle, WA 98195;
authors.forename: José A
authors.initials: JA
authors.lastname: López
authors.affiliation: Cardiovascular Research Section, Department of Medicine, Baylor College of Medicine, Houston, TX 77030;
authors.forename: Christie M
authors.initials: CM
authors.lastname: Ballantyne
authors.affiliation: Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR 72205.
authors.forename: Jerry
authors.initials: J
authors.lastname: Ware
authors.affiliation: Cardiovascular Research Section, Department of Medicine, Baylor College of Medicine, Houston, TX 77030;
authors.forename: Huaizhu
authors.initials: H
authors.lastname: Wu
authors.affiliation: Cardiovascular Research Section, Department of Medicine, Baylor College of Medicine, Houston, TX 77030; Yuandong@bcm.edu.
authors.forename: Yuandong
authors.identifier: 0000-0003-0359-0029
authors.initials: Y
authors.lastname: Peng
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology*; D001792:Blood Platelets / Q000276:immunology*; D016466:CHO Cells; D002135:Calcium-Binding Proteins; D003412:Cricetulus; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006028:Glycosphingolipids / Q000378:metabolism*; D021962:Membrane Microdomains / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008840:Microfilament Proteins; D058226:Plaque, Atherosclerotic / Q000276:immunology*; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000378:metabolism*; D011485:Protein Binding; D013927:Thrombosis / Q000276:immunology*; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: C112986:AIF1 protein, human; D001057:Apolipoproteins E; D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; D006028:Glycosphingolipids; D008840:Microfilament Proteins; D019038:Platelet Glycoprotein GPIb-IX Complex; D014841:von Willebrand Factor