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 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.

Biphasic Effects of 15-Deoxy-Δ 12,14 -Prostaglandin J 2 on Glutathione Induction and Apoptosis in Human Endothelial Cells

“…27 The proapoptotic effects of HNE are well documented in a number of cell types, including endothelial cells. 25,26 In the present study, low concentrations of 15d-PGJ 2 were protective against toxic effects of HNE. This effect was partially inhibited by BSO, suggesting that GSH contributes to the cytoprotective effects of 15d-PGJ 2 .…”

“…To address this, HUVECs were first treated with 15d-PGJ 2 for 24 hours, after which the cells were washed with HBSS and incubated further with HNE. This lipid peroxidation product has been shown to induce apoptosis in a number of cell types, including HUVECs, 25,26 and it is present in human atherosclerotic lesions. 27 Incubation with 15 mol/L HNE caused a statistically significant (PϽ0.05 versus untreated control) increase in the apoptotic cell population.…”

Self-regulatory role of 4-hydroxynonenal in signaling for stress-induced programmed cell death

“…Jurkat cells Down regulation of Akt kinase [52] Neurons NGF withdrawal-induced neuronal apoptosis [53] Chlamydia pneumoniae Inhibition of IKK/I kappa B-mediated signaling [54] HBE1 cells Induction of glutamate cysteine ligase through JNK [55] Human lung fibroblasts Activation of epidermal growth factor receptor-linked extracellular signal kinase p44/42 pathway [56] Retinal pigment epithelial cells Induction of vascular endothelial growth factor [57] Macrophages Activation of PKC beta isoforms [58] K562 cells Role in adaptive response of cells to heat and oxidative stress [7] Vascular smooth muscle cells Prevents NO production [59] Vascular smooth muscle cells NF-kappaB activation and formation of isoprostane [60] PC12 cells Activation of JNK pathway [61] Neurons Inhibits constitutive and inducible activity of NF-Kappa B [62] Hepatic stellate cells Reduces tyrosine phosphorylation [63] Human epidermoid carcinoma A431 cells…”

Inflammation-related gene expression by lipid oxidation-derived products in the progression of atherosclerosis

“…Addition of HNE to macrophages did not modify the constitutive extent of NF-B nuclear translocation [140]. In contrast, net stimulation of NF-B by HNE was demonstrated in vascular SMCs [141].…”