4-hydroxynonenal (HNE) is a lipid hydroperoxide end product formed from the oxidation of n-6 polyunsaturated fatty acids. The relative abundance of HNE within the vasculature is dependent not only on the rate of lipid peroxidation and HNE synthesis but also on the removal of HNE adducts by phase II metabolic pathways such as glutathione-S-transferases. Depending on its relative concentration, HNE can induce a range of hormetic effects in vascular endothelial and smooth muscle cells, including kinase activation, proliferation, induction of phase II enzymes and in high doses inactivation of enzymatic processes and apoptosis. HNE also plays an important role in the pathogenesis of vascular diseases such as atherosclerosis, diabetes, neurodegenerative disorders and in utero diseases such as pre-eclampsia. This review examines the known production, metabolism and consequences of HNE synthesis within vascular endothelial and smooth muscle cells, highlighting alterations in mitochondrial and endoplasmic reticulum function and their association with various vascular pathologies.
Keywords: 15d-PGJ2, 15-deoxy-Delta (12,14) prostaglandin-J2; 4-hydroxynonenal; AP-1, Activator protein-1; AR, Aldose reductase; ARE, Antioxidant response element; ATF6, Activating transcription factor 6; Akt, Protein kinase B; BAEC, Bovine aortic endothelial cells; BH4, Tetrahydrobiopterin; BLMVEC, Bovine lung microvascular vein endothelial cells; BPAEC, Bovine pulmonary arterial endothelial cells; BTB, Broad complex Tramtrack and Bric–brac domain; CHOP, C/EBP-homologous protein; CREB, cAMP response element-binding protein; EGFR, Epidermal growth factor receptor; ER, Endoplasmic reticulum; ERAD, Endoplasmic reticulum assisted degradation; ERK1/2, Extracellular signal-regulated kinase 1/2; Elk1, ETS domain-containing protein; Endothelial cells; EpRE, Electrophile response element; FAK, Focal adhesion kinase; FAP, Familial amyloidotic polyneuropathy; GCLC, Glutamate cysteine ligase catalytic subunit; GCLM, Glutamate cysteine ligase modifier subunit; GS-DHN, Glutathionyl-1,4 dihydroxynonene; GS-HNE, HNE-conjugates; GSH, Glutathione; GST, Glutathione-S-transferase; GTPCH, Guanosine triphosphate cyclohydrolase I; HASMC, Human aortic smooth muscle cells; HCSMC, Human coronary smooth muscle cells; HERP, Homocysteine inducible ER protein; HMEC, Human microvascular endothelial cells; HNE, 4-hydroxynonenal; HO-1, Heme oxygenase-1; HUVEC, Human umbilical vein endothelial cells; Hsp-70/72/90, Heat shock proteins-70/ -72/ -90; IRE1, Inositol requiring enzyme 1 IRE1; IVR, Central intervening region; JNK, c-jun N-terminal kinase; Keap1, Kelch-like ECH-associated protein 1; MASMC, Mouse aortic smooth muscle cells; MEK1/2, Mitogen activated protein kinase kinase 1/2; MMP-1/2, Matrix metalloproteinase-1/ -2; MPEC, Mouse pancreatic islet endothelial cells; NAC, N-acetylcysteine; NFκB, Nuclear factor kappa B; NO, Nitric oxide; NQO1, NAD(P)H quinone oxidoreductase; Nrf2; Nrf2, Nuclear factor-E2-related factor 2; PCEC, Porcine cerebral endothelial cells; PDGF, Platelet-derived growth factor; PDI, Protein disulfide isomerases; PERK, Protein kinase-like endoplasmic reticulum kinase; PKC, Protein kinase C; PUFAs, Polyunsaturated fatty acids; RASMC, Rat aortic smooth muscle cells; ROS, Reactive oxygen species; RVSMC, Rat vascular smooth muscle cells; Redox signaling; SMC, Smooth muscle cell; TKR, Tyrosine kinase receptor; UPR, Unfolded protein response; Vascular biology; Vascular smooth muscle cells; eNOS, Endothelial nitric oxide synthase; elF2α, Eukaryotic translation initiation factor 2α; iNOS, Inducible nitric oxide synthase; oxLDL, Oxidized low density lipoprotein; tBHP, Tert-butylhydroperoxide; xCT, cystine/glutamate amino acid transporter.