Cross-Talk of Receptor Activator of Nuclear Factor-κB Ligand Signaling With Renin–Angiotensin System in Vascular Calcification
Objective—Vascular calcification is accelerated by hypertension and also contributes to hypertension; however, it is an enigma why hypertension and vascular calcification are a vicious spiral. The present study elucidates the cross-talk between renin–angiotensin II system and receptor activator of nuclear factor-κB ligand (RANKL) system in vascular calcification.
Approach and Results—Angiotensin (Ang) II (10−7 mol/L) significantly increased calcium deposition as assessed by Alizarin Red staining, associated with a significant increase in the expression of RANKL, RANK, and bone-related genes, such as cbfa1 and msx2, in human aortic vascular smooth muscle cells. Infusion of Ang II (100 ng/kg per minute) in ovariectomized ApoE−/− mice under high-fat diet significantly increased the expression of RANKL system and calcification in vivo, whereas administration of Ang II receptor blocker (olmesartan, 3 mg/kg per day) decreased the calcification and bone markers’ expression. In addition, male OPG−/− mice showed a significant increase in vascular calcification followed by Ang II infusion as compared with wild type. Conversely, RANKL significantly increased Ang II type 1 receptor and angiotensin II–converting enzyme expression in vascular smooth muscle cells via extracellular signal–regulated protein kinase phosphorylation.
Conclusions—The present study demonstrated that Ang II significantly induced vascular calcification in vitro and in vivo through RANKL activation. In addition, RANKL activated renin–angiotensin II system, especially angiotensin II–converting enzyme and Ang II type 1 receptor. Cross-talk between renin–angiotensin II system and RANKL system might work as a vicious cycle to promote vascular calcification in atherosclerosis. Further studies to inhibit renin–angiotensin II system and RANKL may provide new therapeutic options to prevent and regress vascular calcification.
- Received December 28, 2013.
- Accepted March 22, 2013.
- © 2013 American Heart Association, Inc.