title: Vitamin D deficiency and exogenous vitamin D excess similarly increase diffuse atherosclerotic calcification in apolipoprotein E knockout mice.
abstract: BACKGROUND
  Observational data associate lower levels of serum vitamin D with coronary artery calcification, cardiovascular events and mortality. However, there is little interventional evidence demonstrating that moderate vitamin D deficiency plays a causative role in cardiovascular disease. This study examined the cardiovascular effects of dietary vitamin D deficiency and of vitamin D receptor agonist (paricalcitol) administration in apolipoprotein E knockout mice.
  
  
  METHODS
  Mice were fed atherogenic diets with normal vitamin D content (1.5 IU/kg) or without vitamin D. Paricalcitol, or matched vehicle, was administered 3× weekly by intraperitoneal injection. Following 20 weeks of these interventions cardiovascular phenotype was characterized by histological assessment of aortic sinus atheroma, soluble markers, blood pressure and echocardiography. To place the cardiovascular assessments in the context of intervention effects on bone, structural changes at the tibia were assessed by microtomography.
  
  
  RESULTS
  Vitamin D deficient diet induced significant reductions in plasma vitamin D (p<0.001), trabecular bone volume (p<0.01) and bone mineral density (p<0.005). These changes were accompanied by an increase in calcification density (number of calcifications per mm(2)) of von Kossa-stained aortic sinus atheroma (461 versus 200, p<0.01). Paricalcitol administration suppressed parathyroid hormone (p<0.001), elevated plasma calcium phosphate product (p<0.005) and induced an increase in calcification density (472 versus 200, p<0.005) similar to that seen with vitamin D deficiency. Atheroma burden, blood pressure, metabolic profile and measures of left ventricular hypertrophy were unaffected by the interventions.
  
  
  CONCLUSIONS
  Vitamin D deficiency, as well as excess, increases atherosclerotic calcification. This phenotype is induced before other measures of cardiovascular pathology associated clinically with vitamin D deficiency. Thus, maintenance of an optimal range of vitamin D signalling may be important for prevention of atherosclerotic calcification.
authors.affiliation: Department of Cardiovascular Science, University of Sheffield, Sheffield, United Kingdom ; Sheffield Kidney Institute, Northern General Hospital, Sheffield, United Kingdom.
authors.forename: Timothy
authors.initials: T
authors.lastname: Ellam
authors.affiliation: Department of Cardiovascular Science, University of Sheffield, Sheffield, United Kingdom.
authors.forename: Abdul
authors.initials: A
authors.lastname: Hameed
authors.affiliation: Department of Infection and Immunity, University of Sheffield, Sheffield, United Kingdom.
authors.forename: Risat
authors.initials: R
authors.lastname: ul Haque
authors.affiliation: Department of Infection and Immunity, University of Sheffield, Sheffield, United Kingdom.
authors.forename: Munitta
authors.initials: M
authors.lastname: Muthana
authors.affiliation: Sheffield Kidney Institute, Northern General Hospital, Sheffield, United Kingdom.
authors.forename: Martin
authors.initials: M
authors.lastname: Wilkie
authors.affiliation: Department of Cardiovascular Science, University of Sheffield, Sheffield, United Kingdom.
authors.forename: Sheila E
authors.initials: SE
authors.lastname: Francis
authors.affiliation: Department of Cardiovascular Science, University of Sheffield, Sheffield, United Kingdom.
authors.forename: Timothy J A
authors.initials: TJ
authors.lastname: Chico
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics*; D002114:Calcinosis / Q000150:complications*; D004032:Diet; D004872:Ergocalciferols / Q000494:pharmacology; D017379:Hypertrophy, Left Ventricular / Q000150:complications; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D058226:Plaque, Atherosclerotic / Q000150:complications* / Q000378:metabolism*; D012850:Sinus of Valsalva / Q000187:drug effects; D014807:Vitamin D / Q000494:pharmacology*; D014808:Vitamin D Deficiency / Q000150:complications*
chemical_list: D001057:Apolipoproteins E; D004872:Ergocalciferols; D014807:Vitamin D; C084656:paricalcitol