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Thromb Haemost 2014; 112(06): 1252-1263
DOI: 10.1160/th14-02-0130
Cardiovascular Biology and Cell Signalling
Schattauer GmbH

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

Ekaterina K. Koltsova
1   Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA
2   Immune Cell Development and Host Defense Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA
,
Prithu Sundd
3   Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
,
Alessandro Zarpellon
4   Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, USA
,
Hui Ouyang
1   Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA
,
Zbigniew Mikulski
1   Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA
,
Antonella Zampolli
4   Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, USA
,
Zaverio M. Ruggeri
4   Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, USA
,
Klaus Ley
1   Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA
› Author Affiliations Financial support: This work was supported by National Institutes of Health NIH RO1 115232 and HL 55798, project 4 to K.L; HL-42846 to Z. M.R; American Heart Association Scientist Development Grants 13SDG14490059 to E. K.K; and 11SDG7340005 to P. S.
Further Information

Publication History

Received: 12 February 2014

Accepted after major revision: 02 June 2014

Publication Date:
18 November 2017 (online)

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Summary

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.

Keywords

Aorta - atherosclerosis - inflammation - myeloid cells - platelets

 

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