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P2Y2 Receptor Deficiency Reduces Vascular Inflammation and Atherosclerosis in Mice
Author(s) -
Seye Cheikh
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.1085.5
Subject(s) - apolipoprotein e , inflammation , endocrinology , knockout mouse , medicine , receptor , chemistry , biology , disease
The P2Y2 receptor (P2Y2R) is a primary regulator of vascular cell adhesion molecule‐1 which plays a key role in recruitment of inflammatory cells in atherosclerosis. The objective of this study was to evaluate the consequence of P2Y2R ablation in the development of atherosclerosis. Methods and results Apolipoprotein E‐deficient (ApoE −/− )mice with genetic ablation of P2Y 2 R developed significantly smaller atherosclerotic lesions in the aortic sinus as compared to Apoe −/− littermates when fed a chow diet. Strikingly, lesions of Apoe −/− /P2Y 2 R −/− mice displayed a sharp decrease in macrophage infiltration and VCAM‐1 immunostaining. ApoE −/− mice exhibited spontaneous high blood levels of soluble VCAM‐1 (sVCAM‐1) and knockout of P2Y 2 Rdrastically lowered sVCAM‐1. Basal levels of sVCAM‐1 were detected by Elisa in primary endothelial cells of ApoE −/− mice but not in those from Apoe −/− /P2Y 2 R −/− mice. The P2Y 2 R agonists induced a rapid release of sVCAM‐1 from cultured endothelial cells from wild type but not P2Y 2 R −/− mice, suggesting that VCAM‐1 is part of a specific shedding pathway mediated through P2Y 2 R activation. Notably, inhibition of the pro‐protein convertase furin or specific knockdown of the metalloproteinase ADAM10 inhibited basal and nucleotide‐stimulated sVCAM‐1 release. Conclusion Inactivation of P2Y 2 R protects against atherosclerosis, suggesting that drugs targeting this receptor could prevent recruitment of inflammatory cells.