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

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 evide...