Apelin/APJ signaling is a critical regulator of statin effects in vascular endothelial cells-brief report

Objective-The endothelial response elicited by the G-protein-coupled receptor pathway involving apelin and APJ predicts an overall vasoprotective effect. As a number of downstream endothelial targets of apelin/APJ signaling are also known to be targeted by statins (3-hydroxy-3-methyl-glutaryl [HMG]-CoA reductase inhibitors) as potential mediators of their known pleiotropic effects, we evaluated for the involvement of apelin/APJ signaling in statin endothelial effects. Methods and Results-We found that disruption of apelin/APJ signaling in endothelial cells leads to significantly decreased expression of Krûppel-like factor 2, endothelial nitric oxide synthase, and thrombomodulin. We found that statin-mediated induction of Krûppel-like factor 2, endothelial nitric oxide synthase, and thrombomodulin expression, as well as inhibition of monocyte-endothelial adhesion, was abrogated by concurrent apelin knockdown. Moreover, we found that statins can transcriptionally regulate APJ in a Krûppel-like factor 2-dependent manner, demonstrating the presence of a positive-feedback loop. Conclusion-Our findings provide a novel mechanism by which the apelin/APJ pathway serves as a critical intermediary that links statin to its pleiotropic effects in regulating endothelial gene targets and function.