title: 4-hydroxynonenal induces apoptosis, NF-kappaB-activation and formation of 8-isoprostane in vascular smooth muscle cells.
abstract: Oxidation of lipids is considered a key feature of atherogenesis. Lipid peroxidation products such as oxidized LDL or the bioactive aldehyde 4-hydroxynonenal (HNE) exert mitogenic effects on vascular smooth muscle cells (VSMC). These effects appear to be concentration-dependent since in addition to our previous reports on growth promotion at lower concentrations we here indicate induction of apoptosis in VSMC by 4-hydroxynonenal (HNE) at higher concentrations (100 micromol/L). In a line with HNE's previously documented effects on key mitogenic signaling elements, we also report on activation by this aldehyde of the redox-sensitive transcription factor NF-kappaB, a key regulator of apoptosis: HNE (1.0 micromol/L) induced DNA-binding of NF-kappaB in VSMC. The effect was inhibited by antioxidants, N-acetylcysteine and pyrrolidine dithio-carbamate. HNE caused phosphorylation but not degradation of the inhibitory subunit IkappaB-alpha. HNE itself acts as an oxidant as was investigated with measurements of 8-isoprostane which ranks among the most valuable available biomarkers of lipid peroxidation: HNE (1.0 micromol/L) increased 8-isoprostane levels in VSMC by 4.5-fold (p < 0.05). Compared to the controls, plasma samples from apoEnull mice exhibited elevated levels of 8-isoprostane (40 pg/mL, 3.2-fold increase) and the combined aldehydes HNE and malonaldehyde (1.5 micromol/L, 2.5-fold increase), (p < 0.05, resp). In addition, immunohistochemistry indicated the presence of HNE-protein adducts in atheroscerlotic lesions of apoEnull mice. Thus HNE is present in atherosclerotic tissue at concentrations that are bioactive in vitro. The data further indicate the involvement of the lipid peroxidation product HNE in atherogenesis.
authors.affiliation: Division of Cardiology, University of Heidelberg, Germany. johannes_ruef@med.uni-heidelberg.de
authors.forename: J
authors.initials: J
authors.lastname: Ruef
authors.forename: M
authors.initials: M
authors.lastname: Moser
authors.forename: C
authors.initials: C
authors.lastname: Bode
authors.forename: W
authors.initials: W
authors.lastname: Kübler
authors.forename: M S
authors.initials: MS
authors.lastname: Runge
mesh_terms: D000447:Aldehydes / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000166:cytology; D001057:Apolipoproteins E / Q000235:genetics; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D003324:Coronary Artery Disease / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000494:pharmacology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D015237:Dinoprost / Q000031:analogs & derivatives / Q000096:biosynthesis* / Q000097:blood; D004305:Dose-Response Relationship, Drug; D028441:F2-Isoprostanes; D006801:Humans; D020672:I-kappa B Proteins; D015227:Lipid Peroxidation / Q000187:drug effects / Q000502:physiology; D008054:Lipid Peroxides / Q000097:blood; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism
chemical_list: D000447:Aldehydes; D001057:Apolipoproteins E; D017077:Culture Media, Conditioned; D015853:Cysteine Proteinase Inhibitors; D004268:DNA-Binding Proteins; D028441:F2-Isoprostanes; D020672:I-kappa B Proteins; D008054:Lipid Peroxides; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D000072000:NF-KappaB Inhibitor alpha; C075750:8-epi-prostaglandin F2alpha; D004247:DNA; D015237:Dinoprost; C027576:4-hydroxy-2-nonenal