title: Lack of vitamin D receptor causes stress-induced premature senescence in vascular smooth muscle cells through enhanced local angiotensin-II signals.
abstract: OBJECTIVE
  The inhibition of the renal renin-angiotensin system by the active form of vitamin D contributes to the cardiovascular health benefits of a normal vitamin D status. Local production of angiotensin-II in the vascular wall is a potent mediator of oxidative stress, prompting premature senescence. Herein, our objective was to examine the impact of defective vitamin D signalling on local angiotensin-II levels and arterial health.
  
  
  METHODS
  Primary cultures of aortic vascular smooth muscle cells (VSMC) from wild-type and vitamin D receptor-knockout (VDRKO) mice were used for the assessment of cell growth, angiotensin-II and superoxide anion production and expression levels of cathepsin D, angiotensin-II type 1 receptor and p57(Kip2). The in vitro findings were confirmed histologically in aortas from wild-type and VDRKO mice.
  
  
  RESULTS
  VSMC from VDRKO mice produced more angiotensin-II in culture, and elicited higher levels of cathepsin D, an enzyme with renin-like activity, and angiotensin-II type 1 receptor, than wild-type mice. Accordingly, VDRKO VSMC showed higher intracellular superoxide anion production, which could be suppressed by cathepsin D, angiotensin-II type 1 receptor or NADPH oxidase antagonists. VDRKO cells presented higher levels of p57(Kip2), impaired proliferation and premature senescence, all of them blunted upon inhibition of angiotensin-II signalling. In vivo studies confirmed higher levels of cathepsin D, angiotensin-II type 1 receptor and p57(Kip2) in aortas from VDRKO mice.
  
  
  CONCLUSIONS
  The beneficial effects of active vitamin D in vascular health could be a result of the attenuation of local production of angiotensin-II and downstream free radicals, thus preventing the premature senescence of VSMC.
authors.affiliation: Experimental Nephrology Laboratory, Department of Experimental Medicine, Biomedical Research Institute of Lleida (IRBLLEIDA), Lleida, Spain.
authors.forename: Petya
authors.initials: P
authors.lastname: Valcheva
authors.affiliation: Experimental Nephrology Laboratory, Department of Experimental Medicine, Biomedical Research Institute of Lleida (IRBLLEIDA), Lleida, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Cardus
authors.affiliation: Experimental Nephrology Laboratory, Department of Experimental Medicine, Biomedical Research Institute of Lleida (IRBLLEIDA), Lleida, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Panizo
authors.affiliation: Experimental Nephrology Laboratory, Department of Experimental Medicine, Biomedical Research Institute of Lleida (IRBLLEIDA), Lleida, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Parisi
authors.affiliation: Experimental Nephrology Laboratory, Department of Experimental Medicine, Biomedical Research Institute of Lleida (IRBLLEIDA), Lleida, Spain.
authors.forename: Milica
authors.initials: M
authors.lastname: Bozic
authors.affiliation: Department of Physiology and Pharmacology, University of Salamanca, Salamanca, Spain.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Lopez Novoa
authors.affiliation: Experimental Nephrology Laboratory, Department of Experimental Medicine, Biomedical Research Institute of Lleida (IRBLLEIDA), Lleida, Spain.
authors.forename: Adriana
authors.initials: A
authors.lastname: Dusso
authors.affiliation: Nephrology Service and UDETMA, University Hospital Arnau de Vilanova, Lleida, Spain.
authors.forename: Elvira
authors.initials: E
authors.lastname: Fernández
authors.affiliation: Experimental Nephrology Laboratory, Department of Experimental Medicine, Biomedical Research Institute of Lleida (IRBLLEIDA), Lleida, Spain. Electronic address: valdivielso@medicina.udl.es.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Valdivielso
mesh_terms: D000804:Angiotensin II / Q000096:biosynthesis / Q000502:physiology; D000818:Animals; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects / Q000502:physiology*; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000378:metabolism; D005260:Female; D008297:Male; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000096:biosynthesis; D018167:Receptors, Calcitriol / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism; D014807:Vitamin D / Q000378:metabolism*
chemical_list: C493965:Cdkn1c protein, mouse; D050761:Cyclin-Dependent Kinase Inhibitor p57; D044140:Receptor, Angiotensin, Type 1; D018167:Receptors, Calcitriol; D013481:Superoxides; D000804:Angiotensin II; D014807:Vitamin D
keywords: Angiotensin-II; ROS; Senescence; VSMC; Vitamin D