In:
Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 116, No. 4 ( 2015-02-13), p. 587-599
Abstract:
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 α IIb β 3 -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 α IIb β 3 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 α IIb β 3 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.
Type of Medium:
Online Resource
ISSN:
0009-7330
,
1524-4571
DOI:
10.1161/CIRCRESAHA.116.304035
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2015
detail.hit.zdb_id:
1467838-X
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