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. 2015 Feb 13;116(4):587-99.
doi: 10.1161/CIRCRESAHA.116.304035. Epub 2014 Dec 3.

Hyperreactivity of junctional adhesion molecule A-deficient platelets accelerates atherosclerosis in hyperlipidemic mice

Ela Karshovska  1 , Zhen Zhao  1 , Xavier Blanchet  1 , Martin M N Schmitt  1 , Kiril Bidzhekov  1 , Oliver Soehnlein  1 , Philipp von Hundelshausen  1 , Nadine J Mattheij  1 , Judith M E M Cosemans  1 , Remco T A Megens  1 , Thomas A Koeppel  1 , Andreas Schober  1 , Tilman M Hackeng  1 , Christian Weber  1 , Rory R Koenen  2
Affiliations

Hyperreactivity of junctional adhesion molecule A-deficient platelets accelerates atherosclerosis in hyperlipidemic mice

Ela Karshovska et al. Circ Res. .

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.

Keywords: atherosclerosis; blood platelets; cell adhesion molecules; inflammation; phosphoprotein phosphatases.

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Comment in

  • Activated platelets jam up the plaque.
    Adrover JM, Hidalgo A. Adrover JM, et al. Circ Res. 2015 Feb 13;116(4):557-9. doi: 10.1161/CIRCRESAHA.115.305823. Circ Res. 2015. PMID: 25677512 No abstract available.

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