title: Marginal dietary zinc deficiency in vivo induces vascular smooth muscle cell apoptosis in large arteries.
abstract: OBJECTIVE
  Dietary zinc deficiency has been associated with the development of atherosclerosis although the effects on vascular smooth muscle cells (VSMCs), important in maintaining atherosclerotic plaque integrity, are unknown. The main aim of this study was to elucidate the effect of a zinc-deficient environment on VSMCs using an in vivo model.
  
  
  RESULTS
  Rats were maintained for 2 weeks on a marginally zinc-deficient diet which resulted in a significant reduction in plasma zinc levels. Large arteries from zinc-deficient rats had significantly increased apoptosis within the VSMC layers compared with arteries from rats on a zinc-adequate diet. This apoptosis occurred in parallel with a known apoptotic pathway, namely dephosphorylation of the pro-apoptotic protein Bcl-2-associated death promoter protein (BAD). Activation of extracellular signal-regulated kinase (ERK)1/2, which maintains BAD phosphorylation as a pro-survival mechanism, was decreased in arteries from zinc-deficient rats. The mechanisms of this in vivo effect were investigated in vitro. Cultured rat VSMCs incubated with plasma from zinc-deficient rats similarly resulted in increased apoptosis in parallel with BAD dephosphorylation and decreased ERK1/2 activation. Further related apoptotic mechanisms induced by plasma from zinc-deficient rats involved a prolonged rise in [Ca²⁺]i leading to subsequent activation of the phosphatase calcineurin. Calcineurin activation was required to dephosphorylate BAD. In addition, an increase in oxidative stress contributed to the apoptotic effect induced by plasma from zinc-deficient rats.
  
  
  CONCLUSIONS
  In conclusion, a marginally zinc-deficient diet is pro-apoptotic for VSMCs and this may contribute to cardiovascular disease.
authors.affiliation: School of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK.
authors.forename: Keith
authors.initials: K
authors.lastname: Allen-Redpath
authors.forename: Ou
authors.initials: O
authors.lastname: Ou
authors.forename: John H
authors.initials: JH
authors.lastname: Beattie
authors.forename: In-Sook
authors.initials: IS
authors.lastname: Kwun
authors.forename: Jorg
authors.initials: J
authors.lastname: Feldmann
authors.forename: Graeme F
authors.initials: GF
authors.lastname: Nixon
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D019703:Calcineurin / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002340:Carotid Artery Diseases / Q000209:etiology* / Q000378:metabolism / Q000473:pathology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D020935:MAP Kinase Signaling System; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology*; D018384:Oxidative Stress; D010766:Phosphorylation; D051381:Rats; D015032:Zinc / Q000097:blood / Q000172:deficiency*; D051025:bcl-Associated Death Protein / Q000378:metabolism
chemical_list: C494821:Bad protein, rat; D051025:bcl-Associated Death Protein; D019703:Calcineurin; D015032:Zinc; D002118:Calcium
keywords: Apoptosis; Artery; Vascular smooth muscle cell; Zinc deficiency