title: Induction of heme oxygenase 1 by moderately oxidized low-density lipoproteins in human vascular smooth muscle cells: role of mitogen-activated protein kinases and Nrf2.
abstract: Oxidized low-density lipoproteins (LDL) play a central role in atherogenesis and induce expression of the antioxidant stress protein heme oxygenase 1 (HO-1). In the present study we investigated induction of HO-1 and adaptive increases in reduced glutathione (GSH) in human aortic smooth muscle cells (SMC) in response to moderately oxidized LDL (moxLDL, 100 microg protein/ml, 24 h), a species containing high levels of lipid hydroperoxides. Expression and activity of HO-1 and GSH levels were elevated to a greater extent by moxLDL than highly oxidized LDL but unaffected by native or acetylated LDL. Inhibitors of protein kinase C (PKC) or mitogen-activated protein kinases (MAPK) p38(MAPK) and MEK or c-jun-NH2-terminal kinase (JNK) significantly attenuated induction of HO-1. Phosphorylation of p38(MAPK), extracellular signal-regulated kinase (ERK1/2), or JNK and nuclear translocation of the transcription factor Nrf2 were enhanced following acute exposure of SMC to moxLDL (100 microg protein/ml, 1-2 h). Pretreatment of SMC with the antioxidant vitamin C (100 microM, 24 h) attenuated the induction of HO-1 by moxLDL. Native and oxidized LDL did not alter basal levels of intracellular ATP, mitochondrial dehydrogenase activity, or expression of the lectin-like oxidized LDL receptor (LOX-1) in SMC. These findings demonstrate for the first time that activation of PKC, p38(MAPK), JNK, ERK1/2, and Nrf2 by oxidized LDL in human SMC leads to HO-1 induction, constituting an adaptive response against oxidative injury that can be ameliorated by vitamin C.
authors.affiliation: Cardiovascular Division, GKT Schools of Biomedical Sciences and Medicine, King's College, University of London, Guy's Hospital Campus, London SE1 1UL, UK.
authors.forename: Anila A
authors.initials: AA
authors.lastname: Anwar
authors.forename: Francois Y L
authors.initials: FY
authors.lastname: Li
authors.forename: David S
authors.initials: DS
authors.lastname: Leake
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Ishii
authors.forename: Giovanni E
authors.initials: GE
authors.lastname: Mann
authors.forename: Richard C M
authors.initials: RC
authors.lastname: Siow
mesh_terms: D021581:Active Transport, Cell Nucleus; D000255:Adenosine Triphosphate / Q000378:metabolism; D000975:Antioxidants / Q000494:pharmacology; D001161:Arteriosclerosis / Q000378:metabolism; D001205:Ascorbic Acid / Q000378:metabolism; D015153:Blotting, Western; D002470:Cell Survival; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000737:chemistry / Q000378:metabolism*; D051547:Heme Oxygenase-1; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D037102:Lectins / Q000378:metabolism; D050356:Lipid Metabolism; D008077:Lipoproteins, LDL / Q000737:chemistry / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008565:Membrane Proteins; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology*; D051267:NF-E2-Related Factor 2; D010100:Oxygen / Q000378:metabolism*; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000975:Antioxidants; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D037102:Lectins; D008077:Lipoproteins, LDL; D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D015534:Trans-Activators; C099252:oxidized low density lipoprotein; D000255:Adenosine Triphosphate; D006861:Hydrogen Peroxide; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D005978:Glutathione; D001205:Ascorbic Acid; D010100:Oxygen