Impact of mitochondrial ROS production on diabetic vascular complications.
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.
Nishikawa
Takeshi
T
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
Kukidome
Daisuke
D
Sonoda
Kazuhiro
K
Fujisawa
Kazuo
K
Matsuhisa
Takako
T
Motoshima
Hiroyuki
H
Matsumura
Takeshi
T
Araki
Eiichi
E
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*
D017382:Reactive Oxygen Species; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003849:Deoxyguanosine