| First Author | Koltsova EK | Year | 2014 |
| Journal | Thromb Haemost | Volume | 112 |
| Issue | 6 | Pages | 1252-63 |
| PubMed ID | 25104056 | Mgi Jnum | J:340843 |
| Mgi Id | MGI:7524469 | Doi | 10.1160/TH14-02-0130 |
| Citation | Koltsova EK, et al. (2014) Genetic deletion of platelet glycoprotein Ib alpha but not its extracellular domain protects from atherosclerosis. Thromb Haemost 112(6):1252-63 |
| abstractText | 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) Ibalpha 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 GPIbalpha in the pathogenesis of atherosclerosis using two unique knockout models. Ldlr-/- mice were reconstituted with wild-type (wt), GPIbalpha-/- (lacks GPIbalpha) or chimeric IL-4R/GPIbalpha-Tg (lacks GPIbalpha extracellular domain) bone marrow and assayed for atherosclerosis development after feeding with pro-atherogenic "western diet". Here, we report that Ldlr-/-mice reconstituted with GPIbalpha-/- 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 GPIbalpha-/- mice, which resulted in decreased monocyte activation. Interestingly, Ldlr-/-mice reconstituted with IL-4R/GPIbalpha-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 GPIbalpha ablation altered platelet microparticles and CCL5 chemokine production. Thus, atherosclerosis reduction in mice lacking GPIbalpha may not result from the defective GPIbalpha-ligand binding, but more likely is a consequence of functional defects of GPIbalpha-/- platelets and reduced blood platelet counts. |
