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 c-Src activation. Upon αIIbβ3 ligation, JAM-A was shown to be dephosphorylated, which could be prevented by PTPN1 inhibition. Mice with or without platelet-specific (tr)JAM-A-deficiency in an apolipoprotein e (apoe-/-) background were fed a high-fat diet. After up to 12 weeks of diet, trJAM-A-/- apoe-/- mice showed increased aortic plaque formation 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 CCL5 and CXCL4 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 pro-inflammatory effects of JAM-A-deficient platelets could be abolished by 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.
- Received March 28, 2014.
- Revision received November 28, 2014.
- Accepted December 2, 2014.