Oxidized low-density lipoprotein (oxLDL) triggers hypoxia-inducible factor-1alpha (HIF-1alpha) accumulation via redox-dependent mechanisms

Blood. 2003 Jun 15;101(12):4847-9. doi: 10.1182/blood-2002-09-2711. Epub 2003 Feb 13.


Oxidized low-density lipoprotein (oxLDL) and macrophages play a central role in atherosclerosis. Here, we obtained evidence that oxLDL induced hypoxia-inducible factor-1alpha (HIF-1alpha) protein accumulation in human macrophages (Mono-Mac-6) under normoxia. HIF-1alpha accumulation was attenuated by pretreatment with the antioxidant N-acetyl-L-cysteine (NAC), the nitric oxide (NO) donor S-nitrosoglutathione (GSNO), and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitors such as diphenyleniodonium (DPI) or 4-(2-aminoethyl)-benzenesulfonyl fluoride (AEBSF), thus implicating the contribution of oxLDL-generated reactive oxygen species (ROS). Whereas oxLDL did not modulate HIF-1alpha mRNA levels, experiments with cycloheximide pointed to a translational mechanism in oxLDL action. HIF-1-dependent luciferase reporter gene analysis underscored HIF-1 transactivation. Our results indicate that oxLDL induced HIF-1alpha accumulation and HIF-1-dependent reporter gene activation in human macrophages via a redox-mediated pathway. This finding may suggest a role of HIF-1 in atherosclerosis and oxLDL-induced pathogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcysteine / pharmacology
  • Antioxidants / pharmacology
  • Cell Line
  • Enzyme Inhibitors / pharmacology
  • Gene Expression / drug effects
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Lipoproteins, LDL / pharmacology*
  • Macrophages / metabolism
  • NADPH Oxidases / antagonists & inhibitors
  • Nitric Oxide Donors / pharmacology
  • Onium Compounds / pharmacology
  • Oxidation-Reduction
  • RNA, Messenger / analysis
  • Reactive Oxygen Species / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • S-Nitrosoglutathione / pharmacology
  • Transcription Factors / biosynthesis*
  • Transcription Factors / genetics
  • Transfection


  • Antioxidants
  • Enzyme Inhibitors
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Lipoproteins, LDL
  • Nitric Oxide Donors
  • Onium Compounds
  • RNA, Messenger
  • Reactive Oxygen Species
  • Transcription Factors
  • oxidized low density lipoprotein
  • S-Nitrosoglutathione
  • diphenyleneiodonium
  • NADPH Oxidases
  • Acetylcysteine