Apelin/APJSignaling 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 the downstream endothelial targets of apelin/APJ signaling are also known to be targeted by statins (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 Krűppel-like factor 2, endothelial nitric oxide synthase, and thrombomodulin. We found that statin-mediated induction of Krűppel-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 Krűppel-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 pleiotropiceffects in regulating endothelial gene targets and function.
- Received May 21, 2012.
- Accepted September 1, 2012.
- © 2012 American Heart Association, Inc.