1. Hyperreactivity of junctional adhesion molecule A-deficient platelets accelerates atherosclerosis in hyperlipidemic mice.
- Author
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Karshovska E, Zhao Z, Blanchet X, Schmitt MM, Bidzhekov K, Soehnlein O, von Hundelshausen P, Mattheij NJ, Cosemans JM, Megens RT, Koeppel TA, Schober A, Hackeng TM, Weber C, and Koenen RR
- Subjects
- Animals, Aorta pathology, Aortic Diseases blood, Aortic Diseases genetics, Aortic Diseases pathology, Apolipoproteins E deficiency, Apolipoproteins E genetics, Atherosclerosis blood, Atherosclerosis genetics, Atherosclerosis pathology, Carotid Artery Diseases blood, Carotid Artery Diseases genetics, Carotid Artery Diseases pathology, Cell Adhesion, Cell Adhesion Molecules blood, Cell Adhesion Molecules genetics, Cells, Cultured, Chemotaxis, Leukocyte, Diet, High-Fat, Disease Models, Animal, Disease Progression, Female, Genotype, Humans, Hyperlipidemias blood, Hyperlipidemias genetics, Inflammation Mediators metabolism, Leukocytes metabolism, Male, Mice, Inbred C57BL, Mice, Knockout, Phenotype, Plaque, Atherosclerotic, Platelet Glycoprotein GPIIb-IIIa Complex metabolism, Protein Tyrosine Phosphatase, Non-Receptor Type 1 metabolism, Receptors, Cell Surface blood, Receptors, Cell Surface genetics, Thrombosis blood, Thrombosis etiology, Time Factors, src-Family Kinases metabolism, Aorta metabolism, Aortic Diseases etiology, Atherosclerosis etiology, Blood Platelets metabolism, Carotid Artery Diseases etiology, Cell Adhesion Molecules deficiency, Hyperlipidemias complications, Platelet Aggregation, Receptors, Cell Surface deficiency
- 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 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-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 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., (© 2014 American Heart Association, Inc.)
- Published
- 2015
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