Oxidized low-density lipoprotein (oxLDL) triggers hypoxia-inducible factor-1alpha (HIF-1alpha) accumulation via redox-dependent mechanisms.
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.
Shatrov
Vladimir A
VA
Faculty of Biology, Department of Cell Biology, University of Kaiserslautern, Germany.
Sumbayev
Vadim V
VV
Zhou
Jie
J
Brüne
Bernhard
B
D000111:Acetylcysteine / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D008264:Macrophages / Q000378:metabolism; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009861:Onium Compounds / Q000494:pharmacology; D010084:Oxidation-Reduction; D012333:RNA, Messenger / Q000032:analysis; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D026422:S-Nitrosoglutathione / Q000494:pharmacology; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D014162:Transfection
D000975:Antioxidants; D004791:Enzyme Inhibitors; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008077:Lipoproteins, LDL; D020030:Nitric Oxide Donors; D009861:Onium Compounds; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D014157:Transcription Factors; C099252:oxidized low density lipoprotein; D026422:S-Nitrosoglutathione; C007517:diphenyleneiodonium; D019255:NADPH Oxidases; D000111:Acetylcysteine