4-Hydroxynonenal induces apoptosis, NF-κB-activation and formation of 8-isoprostane in vascular smooth nmuscle 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 μmol/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-κB, a key regulator of apoptosis: HNE (1.0 μmol/L) induced DNA-binding of NFκB in VSMC. The effect was inhibited by antioxidants, N-acetylcysteine and pyrrolidine dithio-carbamate. HNE caused phosphorylation but not degradation of the inhibitory subunit IκB-α. 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 μmol/L) increased 8-isoprostane levels in VSMC by 4.5-fold (p < 0.05). Compared to the controls, plasma samples from apoE^null mice exhibited elevated levels of 8-isoprostane (40 pg/mL, 3.2-fold increase) and the combined aldehydes HNE and malonaldehyde (1.5 μmol/L, 2.5-fold increase), (p < 0.05, resp.). In addition, immunohistochemistry indicated the presence of HNE-protein adducts in atheroscerlotic lesions of apoE^null 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.