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Medical AI Inquiry: You was designed to assist in medical decision-making based on the provided user questions. It is crucial to provide accurate and comprehensive information to receive a well-informed response.  Labels: BACKGROUND, OBJECTIVE, RESULTS. Meshes: Animals, Aorta, Aortic Diseases, Apolipoproteins E, Atherosclerosis, Blood Platelets, Carotid Artery Diseases, Cell Adhesion, Cell Adhesion Molecules, Cells, Cultured, Chemotaxis, Leukocyte, Diet, High-Fat, Disease Models, Animal, Disease Progression, Female, Genotype, Humans, Hyperlipidemias, Inflammation Mediators, Leukocytes, Male, Mice, Inbred C57BL, Mice, Knockout, Phenotype, Plaque, Atherosclerotic, Platelet Aggregation, Platelet Glycoprotein GPIIb-IIIa Complex, Protein Tyrosine Phosphatase, Non-Receptor Type 1, Receptors, Cell Surface, Thrombosis, Time Factors, src-Family Kinases.
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Does hyperreactivity of junctional adhesion molecule A-deficient platelets accelerate atherosclerosis in hyperlipidemic mice? Context: 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. This gain-of-function was specifically exploited to investigate the role of platelet hyperreactivity in plaque development. 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.
assistant
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. Final Decision: yes