title: Impact of mitochondrial ROS production on diabetic vascular complications.
abstract: Vascular complications are the leading cause of morbidity and mortality in patients with diabetes. Four main molecular mechanisms have been implicated in glucose-mediated vascular disease. There are: glucose-induced activation of protein kinase C (PKC) isoforms; increased formation of glucose-derived advanced glycation end-products (AGE); increased glucose flux through the aldose reductase pathway; and increased production of reactive oxygen species (ROS). Here we demonstrate that hyperglycemia-induced production of ROS is abrogated by inhibitors of mitochondrial metabolism, or by overexpression of uncoupling protein-1 or manganese superoxide dismutase. Normalization of mitochondrial ROS production by each of these agents prevents glucose-induced activation of PKC, formation of AGE, and accumulation of sorbitol in bovine vascular endothelial cells. We also claim that 8-hydroxydeoxyguanosine, which represents mitochondrial oxidative damage was elevated in patients with either retinopathy, albuminuria or increased intima-media thickness of carotid arteries. These results suggest that hyperglycemia induces mitochondrial ROS production, and which can associate to the pathogenesis of diabetic vascular complications.
authors: Department of Metabolic Medicine, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan. takeshi@kaiju.medic.kumamoto-u.ac.jp
authors: Takeshi
authors: T
authors: Nishikawa
authors: Daisuke
authors: D
authors: Kukidome
authors: Kazuhiro
authors: K
authors: Sonoda
authors: Kazuo
authors: K
authors: Fujisawa
authors: Takako
authors: T
authors: Matsuhisa
authors: Hiroyuki
authors: H
authors: Motoshima
authors: Takeshi
authors: T
authors: Matsumura
authors: Eiichi
authors: E
authors: Araki
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D002952:Citric Acid Cycle; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D003925:Diabetic Angiopathies / Q000503:physiopathology*; D006801:Humans; D008928:Mitochondria / Q000502:physiology*; D008954:Models, Biological; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003849:Deoxyguanosine