The antagonist of P2Y11 receptor NF157 ameliorates oxidized LDL-induced vascular endothelial inflammation.

Atherosclerosis is the chronic inflammatory disease, and inflammation-elicited endothelial activation is an early event in the development of atherosclerosis. The P2Y11 receptor is a purinergic receptor and a member of the P2 family of G coupled protein which has been shown to modulate vascular function. Progress in the study of purine receptors has been tremendous and these receptors have become pharmacological targets for various diseases. In this study, we show that the P2Y11R antagonist NF157 can mitigate oxidized LDL (ox-LDL)-induced endothelial inflammation. Our study demonstrates that P2Y11R is expressed to a fair degree in human aortic endothelial cells and is induced by treatment with ox-LDL. Blockage of P2Y11R by its selective antagonist NF157 ameliorates ox-LDL-induced adhesion of THP-1 monocytes to endothelial cells. NF157 inhibits ox-LDL-induced expression of adhesion molecules including E-selectin and VCAM-1. NF157 also suppresses ox-LDL-associated ROS production and induction of the NADPH oxidase subunit NOX-4. Moreover, NF157 has an inhibitory effect on the production of major cytokines including IL-6 and TNF-α. Mechanistically, we show that NF157 mitigates ox-LDL-induced phosphorylation of MAPK kinase p38 and NF-κB activation. Our findings indicate that blockage of P2Y11R signalling by its antagonist NF157 may protect endothelial cells from ox-LDL-induced endothelial inflammation. Therefore, NF157 may have therapeutic implications in the modulation of atherosclerosis-associated inflammation.