title: Hypoxia is present in murine atherosclerotic plaques and has multiple adverse effects on macrophage lipid metabolism.
abstract: BACKGROUND
  Human atherosclerotic plaques contain large numbers of cells deprived of O(2). In murine atherosclerosis, because the plaques are small, it is controversial whether hypoxia can occur.
  
  
  OBJECTIVE
  To examine if murine plaques contain hypoxic cells, and whether hypoxia regulates changes in cellular lipid metabolism and gene expression in macrophages.
  
  
  RESULTS
  Aortic plaques from apolipoprotein-E-deficient mice were immunopositive for hypoxia-inducible transcription factor (HIF-1α) and some of its downstream targets. Murine J774 macrophages rendered hypoxic demonstrated significant increases in cellular sterol and triglycerides. The increase in sterol content in hypoxic macrophages correlated with elevated 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase activity and mRNA levels. In addition, when macrophages were incubated with cholesterol complexes, hypoxic cells accumulated 120% more cholesterol, predominately in the free form. Cholesterol-efflux assays showed that hypoxia significantly decreased efflux mediated by ATP-binding cassette subfamily A member 1 (ABCA1), whose sub cellular localization was altered in both J774 and primary macrophages. Furthermore, in vivo expression patterns of selected genes from cells in hypoxic regions of murine plaques were similar to those from J774 and primary macrophages incubated in hypoxia. The hypoxia-induced accumulation of sterol and decreased cholesterol efflux was substantially reversed in vitro by reducing the expression of the hypoxia-inducible transcription factor, HIF-1α.
  
  
  CONCLUSIONS
  Hypoxic regions are present in murine plaques. Hypoxic macrophages have increased sterol content due to the induction of sterol synthesis and the suppression of cholesterol efflux, effects that are in part mediated by HIF-1α.
authors.affiliation: NYU School of Medicine, Departments of Medicine (Cardiology) and Cell Biology, Marc and Ruti Bell Program in Vascular Biology, New York, NY 10016, USA.
authors.forename: Sajesh
authors.initials: S
authors.lastname: Parathath
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Mick
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Feig
authors.forename: Victor
authors.initials: V
authors.lastname: Joaquin
authors.forename: Lisa
authors.initials: L
authors.lastname: Grauer
authors.forename: David M
authors.initials: DM
authors.lastname: Habiel
authors.forename: Max
authors.initials: M
authors.lastname: Gassmann
authors.forename: Lawrence B
authors.initials: LB
authors.lastname: Gardner
authors.forename: Edward A
authors.initials: EA
authors.lastname: Fisher
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism*; D001692:Biological Transport; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics / Q000378:metabolism; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D058226:Plaque, Atherosclerotic / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D014162:Transfection
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D001057:Apolipoproteins E; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases