Hyperreactivity of Junctional Adhesion Molecule A-Deficient Platelets Accelerates Atherosclerosis in Hyperlipidemic Mice

• Published in: Circulation research 2015-02, Vol.116 (4), p.587-599
• Main 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
• Format: Article
• Language: English
• Subjects: Animals; Aorta - metabolism; Aorta - pathology; Aortic Diseases - blood; Aortic Diseases - etiology; Aortic Diseases - genetics; Aortic Diseases - pathology; Apolipoproteins E - deficiency; Apolipoproteins E - genetics; Atherosclerosis - blood; Atherosclerosis - etiology; Atherosclerosis - genetics; Atherosclerosis - pathology; Blood Platelets - metabolism; Carotid Artery Diseases - blood; Carotid Artery Diseases - etiology; Carotid Artery Diseases - genetics; Carotid Artery Diseases - pathology; Cell Adhesion; Cell Adhesion Molecules - blood; Cell Adhesion Molecules - deficiency; Cell Adhesion Molecules - genetics; Cells, Cultured; Chemotaxis, Leukocyte; Diet, High-Fat; Disease Models, Animal; Disease Progression; Female; Genotype; Humans; Hyperlipidemias - blood; Hyperlipidemias - complications; Hyperlipidemias - genetics; Inflammation Mediators - metabolism; Leukocytes - metabolism; Male; Mice, Inbred C57BL; Mice, Knockout; Phenotype; Plaque, Atherosclerotic; Platelet Aggregation; Platelet Glycoprotein GPIIb-IIIa Complex - metabolism; Protein Tyrosine Phosphatase, Non-Receptor Type 1 - metabolism; Receptors, Cell Surface - blood; Receptors, Cell Surface - deficiency; Receptors, Cell Surface - genetics; src-Family Kinases - metabolism; Thrombosis - blood; Thrombosis - etiology; Time Factors
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/CIRCRESAHA.116.304035

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 αIIbβ3-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 αIIbβ3 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-Aapoe–/– 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 apoemice, 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 apoemice. Notably, these proinflammatory effects of JAM-A–deficient platelets could be abolished by the inhibition of αIIbβ3 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.