Journal
MOLECULAR IMMUNOLOGY
Volume 106, Issue -, Pages 29-35Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.molimm.2018.12.009
Keywords
Neurokinin-1 receptor; Aprepitant; Oxidized LDL; Endothelial dysfunction; KLF2; ERK5
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Atherosclerosis is the main cause of many cardiovascular diseases. Endothelial dysfunction is recognized as an early event in the development of atherosclerosis. Many drugs have been studied to mitigate hyperlipidemia-induced endothelial injury. Studies have demonstrated that neuropeptide substance P (SP) and its preferred receptor neurokinin receptor 1 (NK-1R) are involved in the pathological progression of cardiovascular disease. In this study, we show that aprepitant, a selective NK-1R antagonist, possesses beneficial effects that protect endothelial cells from oxidized low-density lipoprotein (ox-LDL)-induced inflammatory response and injury. Our data demonstrate that NK-1R is expressed in both aortic and vein-originated endothelial cells and that ox-LDL treatment induces NK-1R expression. Treatment with aprepitant suppresses induction of endothelial vascular adhesion molecule (VCAM-1 and E-selectin) and cytokine by ox-LDL. The presence of aprepitant mitigates adhesion of monocytes to endothelial cells and the reduction in eNOS/NO triggered by ox-LDL. Mechanistically, we demonstrate that aprepitant suppresses ERK5-KLF2 axis activation. Silencing of KLF2 abolishes the inhibitory role of aprepitant on ox-LDL-induced inflammatory response, suggesting that its action is dependent on KLF2. Collectively, our data support that aprepitant exerts an anti-inflammatory effect. Further research is required to investigate the therapeutic potential of aprepitant in vascular inflammation resulting from atherosclerosis.
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