title: Cross-talk of receptor activator of nuclear factor-κB ligand signaling with renin-angiotensin system in vascular calcification.
abstract: 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.
  
  
  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.
authors.affiliation: Division of Vascular Medicine and Epigenetics, United Graduate School of Child Development, Osaka University, Suita, Japan.
authors.forename: Mariana Kiomy
authors.initials: MK
authors.lastname: Osako
authors.forename: Hironori
authors.initials: H
authors.lastname: Nakagami
authors.forename: Munehisa
authors.initials: M
authors.lastname: Shimamura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Koriyama
authors.forename: Futoshi
authors.initials: F
authors.lastname: Nakagami
authors.forename: Hideo
authors.initials: H
authors.lastname: Shimizu
authors.forename: Takashi
authors.initials: T
authors.lastname: Miyake
authors.forename: Masao
authors.initials: M
authors.lastname: Yoshizumi
authors.forename: Hiromi
authors.initials: H
authors.lastname: Rakugi
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Morishita
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D053245:RANK Ligand / Q000378:metabolism* / Q000502:physiology; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000378:metabolism* / Q000502:physiology; D020239:Receptor Cross-Talk / Q000502:physiology*; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000502:physiology*; D012680:Sensitivity and Specificity; D015398:Signal Transduction; D061205:Vascular Calcification / Q000378:metabolism*
chemical_list: D001057:Apolipoproteins E; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D044140:Receptor, Angiotensin, Type 1
keywords: angiotensin II; calcification; receptor activator of nuclear factor-κB ligand; serum osteoprotegerin