title: Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage.
abstract: Diabetic hyperglycaemia causes a variety of pathological changes in small vessels, arteries and peripheral nerves. Vascular endothelial cells are an important target of hyperglycaemic damage, but the mechanisms underlying this damage are not fully understood. Three seemingly independent biochemical pathways are involved in the pathogenesis: glucose-induced activation of protein kinase C isoforms; increased formation of glucose-derived advanced glycation end-products; and increased glucose flux through the aldose reductase pathway. The relevance of each of these pathways is supported by animal studies in which pathway-specific inhibitors prevent various hyperglycaemia-induced abnormalities. Hyperglycaemia increases the production of reactive oxygen species inside cultured bovine aortic endothelial cells. Here we show that this increase in reactive oxygen species is prevented by an inhibitor of electron transport chain complex II, by an uncoupler of oxidative phosphorylation, by uncoupling protein-1 and by manganese superoxide dismutase. Normalizing levels of mitochondrial reactive oxygen species with each of these agents prevents glucose-induced activation of protein kinase C, formation of advanced glycation end-products, sorbitol accumulation and NFkappaB activation.
authors.affiliation: Albert Einstein College of Medicine, Diabetes Research Centre, Bronx, New York 10461, USA.
authors.forename: T
authors.initials: T
authors.lastname: Nishikawa
authors.forename: D
authors.initials: D
authors.lastname: Edelstein
authors.forename: X L
authors.initials: XL
authors.lastname: Du
authors.forename: S
authors.initials: S
authors.lastname: Yamagishi
authors.forename: T
authors.initials: T
authors.lastname: Matsumura
authors.forename: Y
authors.initials: Y
authors.lastname: Kaneda
authors.forename: M A
authors.initials: MA
authors.lastname: Yorek
authors.forename: D
authors.initials: D
authors.lastname: Beebe
authors.forename: P J
authors.initials: PJ
authors.lastname: Oates
authors.forename: H P
authors.initials: HP
authors.lastname: Hammes
authors.forename: I
authors.initials: I
authors.lastname: Giardino
authors.forename: M
authors.initials: M
authors.lastname: Brownlee
mesh_terms: D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D002352:Carrier Proteins / Q000494:pharmacology; D002417:Cattle; D004579:Electron Transport; D042963:Electron Transport Complex II; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004789:Enzyme Activation; D017127:Glycation End Products, Advanced / Q000378:metabolism; D006943:Hyperglycemia / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D007473:Ion Channels; D008293:Malates / Q000378:metabolism; D008565:Membrane Proteins / Q000494:pharmacology; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins; D009097:Multienzyme Complexes / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010088:Oxidoreductases / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012402:Rotenone / Q000494:pharmacology; D013012:Sorbitol / Q000378:metabolism; D013385:Succinate Dehydrogenase / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism / Q000494:pharmacology; D013804:Thenoyltrifluoroacetone / Q000031:analogs & derivatives / Q000494:pharmacology; D014475:Uncoupling Agents / Q000494:pharmacology; D000071256:Uncoupling Protein 1
chemical_list: D001786:Blood Glucose; D002352:Carrier Proteins; D017127:Glycation End Products, Advanced; D007473:Ion Channels; D008293:Malates; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D009097:Multienzyme Complexes; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D014475:Uncoupling Agents; D000071256:Uncoupling Protein 1; D012402:Rotenone; C009472:thiothenoyltrifluoroacetone; D001224:Aspartic Acid; D013804:Thenoyltrifluoroacetone; D013012:Sorbitol; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; C030298:malic acid; D010088:Oxidoreductases; D013482:Superoxide Dismutase; D042963:Electron Transport Complex II; D013385:Succinate Dehydrogenase; D011493:Protein Kinase C