Evidence for contribution of vascular NAD(P)H oxidase to increased oxidative stress in animal models of diabetes and obesity.
It is well established that oxidative stress is enhanced in diabetes. However, the major in vivo source of oxidative stress is not clear. Here we show that vascular NAD(P)H oxidase may be a major source of oxidative stress in diabetic and obese models. In vivo electron spin resonance (ESR)/spin probe was used to evaluate systemic oxidative stress in vivo. The signal decay rate of the spin probe (spin clearance rate; SpCR) significantly increased in streptozotocin-induced diabetic rats 2 weeks after the onset of diabetes. This increase was completely normalized by treatment with the antioxidants alpha-tocopherol (40 mg/kg) and superoxide dismutase (5000 units/kg), and was significantly inhibited by treatment with a PKC-specific inhibitor, CGP41251 (50 mg/kg), and a NAD(P)H oxidase inhibitor, apocynin (5 mg/kg). Both obese ob/ob mice (10 weeks old) with mild hyperglycemia and Zucker fatty rats (11 weeks old) with normoglycemia exhibited significantly increased SpCR as compared with controls. Again, this increase was inhibited by treatment with both CGP41251 and apocynin. Oral administration of insulin sensitizer, pioglitazone (10 mg/kg), for 7 days also completely normalized SpCR values. These results suggest that vascular NAD(P)H oxidase may be a major source of increased oxidative stress in diabetes and obesity.
Sonta
Toshiyo
T
Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Inoguchi
Toyoshi
T
Tsubouchi
Hirotaka
H
Sekiguchi
Naotaka
N
Kobayashi
Kunihisa
K
Matsumoto
Shingo
S
Utsumi
Hideo
H
Nawata
Hajime
H
D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology*; D004195:Disease Models, Animal; D004578:Electron Spin Resonance Spectroscopy; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005609:Free Radicals / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008297:Male; D009097:Multienzyme Complexes / Q000187:drug effects / Q000378:metabolism*; D009247:NADH, NADPH Oxidoreductases / Q000187:drug effects / Q000378:metabolism*; D019255:NADPH Oxidases / Q000187:drug effects / Q000378:metabolism*; D009765:Obesity / Q000201:enzymology* / Q000235:genetics; D018384:Oxidative Stress / Q000502:physiology*; D000077205:Pioglitazone; D051381:Rats; D017208:Rats, Wistar; D011924:Rats, Zucker; D019311:Staurosporine / Q000031:analogs & derivatives* / Q000494:pharmacology; D045162:Thiazolidinediones / Q000494:pharmacology; D013851:Thinness
D004791:Enzyme Inhibitors; D005609:Free Radicals; D007004:Hypoglycemic Agents; D009097:Multienzyme Complexes; D045162:Thiazolidinediones; C023107:NADH oxidase; D009247:NADH, NADPH Oxidoreductases; D019255:NADPH Oxidases; D019311:Staurosporine; C059539:midostaurin; D000077205:Pioglitazone