title: Hypoxia enhances lipid uptake in macrophages: role of the scavenger receptors Lox1, SRA, and CD36.
abstract: OBJECTIVE
  The core of advanced atherosclerotic plaques turns hypoxic as the arterial wall thickens and oxygen diffusion capacity becomes impaired. Macrophage-derived foam cells play a pivotal role in atherosclerotic plaque formation by expressing scavenger receptors that regulate lipid uptake. However, the role of hypoxia in scavenger receptor regulation remains incompletely understood.
  
  
  RESULTS
  Using RT-qPCR, flow cytometry and immunoblotting, we found that mRNA and protein expression levels of the scavenger receptor A (SRA) and the cluster of differentiation 36 (CD36) were upregulated by oxidized low-density lipoprotein (oxLDL), but decreased following exposure of macrophages to hypoxia. In contrast, lectin-like oxLDL receptor (Lox-1) mRNA and protein levels were upregulated under hypoxic conditions. Flow cytometry confirmed the increased lipid content in macrophages after exposure to 0.2% oxygen and the hypoxia-mimetic dimethyloxalylglycine (DMOG). Antibody-mediated blocking of Lox-1 receptor decreased the hypoxic induction of oxLDL uptake and lipid content. RNAi-mediated knock-down of hypoxia-inducible factor (HIF)-1α in macrophages attenuated the hypoxic induction of Lox-1.
  
  
  CONCLUSIONS
  Hypoxia increases lipid uptake into macrophages and differentially regulates the expression of oxLDL receptors. Lox-1 plays a major role in hypoxia-induced foam cell formation which is, at least in part, mediated by HIF-1α.
authors.affiliation: Cellular Oxygen Physiology, Institute of Physiology, University of Zurich, Switzerland.
authors.forename: Margot
authors.initials: M
authors.lastname: Crucet
authors.forename: Sophia J A
authors.initials: SJ
authors.lastname: Wüst
authors.forename: Patrick
authors.initials: P
authors.lastname: Spielmann
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Lüscher
authors.forename: Roland H
authors.initials: RH
authors.lastname: Wenger
authors.forename: Christian M
authors.initials: CM
authors.lastname: Matter
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D050197:Atherosclerosis / Q000378:metabolism* / Q000503:physiopathology; D001692:Biological Transport / Q000502:physiology; D018955:CD36 Antigens / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000378:metabolism; D005487:Foam Cells / Q000378:metabolism; D055785:Gene Knockdown Techniques; D000860:Hypoxia / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D050356:Lipid Metabolism / Q000502:physiology*; D008077:Lipoproteins, LDL / Q000378:metabolism; D008113:Liver Neoplasms; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D051379:Mice; D012333:RNA, Messenger / Q000378:metabolism; D051117:Scavenger Receptors, Class A / Q000235:genetics / Q000378:metabolism*; D051127:Scavenger Receptors, Class E / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D019138:Antibodies, Blocking; D018955:CD36 Antigens; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008077:Lipoproteins, LDL; C495140:Msr1 protein, mouse; C495138:Olr1 protein, mouse; D012333:RNA, Messenger; D051117:Scavenger Receptors, Class A; D051127:Scavenger Receptors, Class E; C099252:oxidized low density lipoprotein; D002784:Cholesterol