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Genetic deletion of platelet glycoprotein Ib alpha but not its extracellular domain protects from atherosclerosis

Academic Article
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Overview

authors

  • Koltsova, E. K.
  • Sundd, P.
  • Zarpellon, A.
  • Ouyang, H.
  • Mikulski, Z.
  • Zampolli, A.
  • Ruggeri, Zaverio
  • Ley, K.

publication date

  • December 2014

journal

  • Thrombosis and Haemostasis  Journal

abstract

  • The pathogenesis of atherosclerosis involves the interplay of haematopoietic, stromal and endothelial cells. Platelet interactions with endothelium and leukocytes are pivotal for atherosclerosis promotion. Glycoprotein (GP) Ib? is the ligand-binding subunit of the platelet GPIb-IX-V receptor complex; its deficiency causes the Bernard-Soulier syndrome (BSS), characterised by absent platelet GPIb-IX-V, macrothrombocytopenia and bleeding. We designed this study to determine the role of platelet GPIb? in the pathogenesis of atherosclerosis using two unique knockout models. Ldlr-/- mice were reconstituted with wild-type (wt), GPIb?-/- (lacks GPIb?) or chimeric IL-4R/GPIb?-Tg (lacks GPIb? extracellular domain) bone marrow and assayed for atherosclerosis development after feeding with pro-atherogenic "western diet". Here, we report that Ldlr-/-mice reconstituted with GPIb?-/- bone marrow developed less atherosclerosis compared to wt controls; accompanied by augmented accumulation of pro-inflammatory CD11b+ and CD11c+ myeloid cells, reduced oxLDL uptake and decreased TNF and IL 12p35 gene expression in the aortas. Flow cytometry and live cell imaging in whole blood-perfused microfluidic chambers revealed reduced platelet-monocyte aggregates in GPIb?-/- mice, which resulted in decreased monocyte activation. Interestingly, Ldlr-/-mice reconstituted with IL-4R/GPIb?-Tg bone marrow, producing less abnormal platelets, showed atherosclerotic lesions similar to wt mice. Platelet interaction with blood monocytes and accumulation of myeloid cells in the aortas were also essentially unaltered. Moreover, only complete GPIb? ablation altered platelet microparticles and CCL5 chemokine production. Thus, atherosclerosis reduction in mice lacking GPIb? may not result from the defective GPIb?-ligand binding, but more likely is a consequence of functional defects of GPIb?-/- platelets and reduced blood platelet counts.
  • The pathogenesis of atherosclerosis involves the interplay of haematopoietic, stromal and endothelial cells. Platelet interactions with endothelium and leukocytes are pivotal for atherosclerosis promotion. Glycoprotein (GP) Ibα is the ligand-binding subunit of the platelet GPIb-IX-V receptor complex; its deficiency causes the Bernard-Soulier syndrome (BSS), characterised by absent platelet GPIb-IX-V, macrothrombocytopenia and bleeding. We designed this study to determine the role of platelet GPIbα in the pathogenesis of atherosclerosis using two unique knockout models. Ldlr-/- mice were reconstituted with wild-type (wt), GPIbα-/- (lacks GPIbα) or chimeric IL-4R/GPIbα-Tg (lacks GPIbα extracellular domain) bone marrow and assayed for atherosclerosis development after feeding with pro-atherogenic "western diet". Here, we report that Ldlr-/-mice reconstituted with GPIbα-/- bone marrow developed less atherosclerosis compared to wt controls; accompanied by augmented accumulation of pro-inflammatory CD11b+ and CD11c+ myeloid cells, reduced oxLDL uptake and decreased TNF and IL 12p35 gene expression in the aortas. Flow cytometry and live cell imaging in whole blood-perfused microfluidic chambers revealed reduced platelet-monocyte aggregates in GPIbα-/- mice, which resulted in decreased monocyte activation. Interestingly, Ldlr-/-mice reconstituted with IL-4R/GPIbα-Tg bone marrow, producing less abnormal platelets, showed atherosclerotic lesions similar to wt mice. Platelet interaction with blood monocytes and accumulation of myeloid cells in the aortas were also essentially unaltered. Moreover, only complete GPIbα ablation altered platelet microparticles and CCL5 chemokine production. Thus, atherosclerosis reduction in mice lacking GPIbα may not result from the defective GPIbα-ligand binding, but more likely is a consequence of functional defects of GPIbα-/- platelets and reduced blood platelet counts.

subject areas

  • Animals
  • Antigens, CD11b
  • Antigens, CD11c
  • Aortic Diseases
  • Atherosclerosis
  • Bernard-Soulier Syndrome
  • Blood Platelets
  • Bone Marrow Transplantation
  • Chemokine CCL5
  • Diet, Western
  • Disease Models, Animal
  • Female
  • Inflammation Mediators
  • Interleukin-12 Subunit p35
  • Lipoproteins, LDL
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Monocytes
  • Platelet Adhesiveness
  • Platelet Glycoprotein GPIb-IX Complex
  • Protein Structure, Tertiary
  • Receptors, Interleukin-4
  • Receptors, LDL
  • Tumor Necrosis Factor-alpha
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Research

keywords

  • Aorta
  • atherosclerosis
  • inflammation
  • myeloid cells
  • platelets
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Identity

International Standard Serial Number (ISSN)

  • 0340-6245

Digital Object Identifier (DOI)

  • 10.1160/th14-02-0130

PubMed ID

  • 25104056
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Additional Document Info

start page

  • 1252

end page

  • 1263

volume

  • 112

issue

  • 6

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