Hyperreactivity of Junctional Adhesion Molecule A-Deficient Platelets Accelerates Atherosclerosis in Hyperlipidemic Mice. Issue 4 (13th February 2015)

• Record Type: Journal Article
• Authors: Karshovska, Ela; Zhao, Zhen; Blanchet, Xavier; Schmitt, Martin M.N.; Bidzhekov, Kiril; Soehnlein, Oliver; von Hundelshausen, Philipp; Mattheij, Nadine J.; Cosemans, Judith M.E.M.; Megens, Remco T.A.; Koeppel, Thomas A.; Schober, Andreas; Hackeng, Tilman M.; Weber, Christian; Koenen, Rory R.
• Is Part Of: Circulation research. Volume 116:Issue 4(2015)
• Publication Date: 2015-02-13
• Subjects: atherosclerosis -- blood platelets -- cell adhesion molecules -- inflammation -- phosphoprotein phosphatases; Cardiovascular system -- Periodicals; Blood -- Circulation -- Periodicals; Blood Circulation; Cardiovascular System; Vascular Diseases; Sang -- Circulation -- Périodiques; Appareil cardiovasculaire -- Périodiques; 612.1
• DOI: 10.1161/CIRCRESAHA.116.304035
• Languages: English
• ISSNs: 0009-7330

Abstract

Abstract : Rationale: : Besides their essential role in hemostasis, platelets also have functions in inflammation. In platelets, junctional adhesion molecule (JAM)-A was previously identified as an inhibitor of integrin αIIb β3 -mediated outside-in signaling and its genetic knockdown resulted in hyperreactivity. Objective: : This gain-of-function was specifically exploited to investigate the role of platelet hyperreactivity in plaque development. Methods and Results: : JAM-A–deficient platelets showed increased aggregation and cellular and sarcoma tyrosine-protein kinase activation. On αIIb β3 ligation, JAM-A was shown to be dephosphorylated, which could be prevented by protein tyrosine phosphatase nonreceptor type 1 inhibition. Mice with or without platelet-specific (tr)JAM-A-deficiency in an apolipoprotein e ( apoe –/– ) background were fed a high-fat diet. After ⩽12 weeks of diet, trJAM-A –/– apoe–/– mice showed increased aortic plaque formation when compared with trJAM-A +/+ apoe –/– controls, and these differences were most evident at early time points. At 2 weeks, the plaques of the trJAM-A –/– apoe –/– animals revealed increased macrophage, T cell, and smooth muscle cell content. Interestingly, plasma levels of chemokines CC chemokine ligand 5 and CXC-chemokine ligand 4 were increased in the trJAM-A –/– apoe –/– mice, and JAM-A–deficient platelets showed increased binding to monocytes and neutrophils. Whole-blood perfusion experiments and intravital microscopy revealed increased recruitment of platelets and monocytes to the inflamed endothelium in blood of trJAM-A –/– apoe –/– mice. Notably, these proinflammatory effects of JAM-A–deficient platelets could be abolished by the inhibition of αIIb β3 signaling in vitro. Conclusions: : Deletion of JAM-A causes a gain-of-function in platelets, with lower activation thresholds and increased inflammatory activities. This leads to an increase of plaque formation, particularly in early stages of the disease. Abstract : Supplemental Digital Content is available in the text.