title: Statin attenuates high glucose-induced and diabetes-induced oxidative stress in vitro and in vivo evaluated by electron spin resonance measurement.
abstract: An increased oxidative stress may contribute to the accelerated atherosclerosis in diabetic patients. Here we show that 3-hydroxy-3-methylglutaryl CoA reductase inhibitor (statin) attenuates a high glucose-induced and a diabetes-induced oxidative stress through inhibition of vascular NAD(P)H oxidase. Exposure of cultured aortic endothelial cells and smooth muscle cells to a high glucose level (450 mg/dl) for 3 days significantly increased oxidative stress compared with a normal glucose level (100 mg/dl), as evaluated by the staining with 2',7'-dichlorofluorescein diacetate and electron spin resonance (ESR) measurement. This increase was completely blocked by the treatment with pitavastatin (5 x 10(-7)M) as well as a NAD(P)H oxidase inhibitor (diphenylene iodonium) or a PKC inhibitor (calphostin C) in parallel with the change of small GTPase Rac-1 activity, a cytosolic regulatory component of NAD(P)H oxidase. Next, using streptozotocin-induced diabetic rats, the effect of pitavastatin on oxidative stress was evaluated by in vivo ESR measurements, which is a sensitive, noninvasive method. Administration of pitavastatin (5 mg/kg/day) for 4 days attenuated the increased oxidative stress in diabetic rats to control levels. In conclusion, pitavastatin attenuated a high glucose-induced and a diabetes-induced oxidative stress in vitro and in vivo. Thus, our data may provide a new insight into antioxidative therapy in diabetes.
authors.affiliation: Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Tsubouchi
authors.forename: Toyoshi
authors.initials: T
authors.lastname: Inoguchi
authors.forename: Toshiyo
authors.initials: T
authors.lastname: Sonta
authors.forename: Naoichi
authors.initials: N
authors.lastname: Sato
authors.forename: Naotaka
authors.initials: N
authors.lastname: Sekiguchi
authors.forename: Kunihisa
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Hideki
authors.initials: H
authors.lastname: Sumimoto
authors.forename: Hideo
authors.initials: H
authors.lastname: Utsumi
authors.forename: Hajime
authors.initials: H
authors.lastname: Nawata
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000652:urine; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D004578:Electron Spin Resonance Spectroscopy; D042783:Endothelial Cells; D004730:Endothelium, Vascular; D005947:Glucose / Q000008:administration & dosage*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008297:Male; D009281:Naphthalenes / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D020830:rac1 GTP-Binding Protein / Q000187:drug effects
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009281:Naphthalenes; D011804:Quinolines; D000080242:8-Hydroxy-2'-Deoxyguanosine; D011493:Protein Kinase C; D020830:rac1 GTP-Binding Protein; D003849:Deoxyguanosine; C058819:calphostin C; D005947:Glucose; C108475:pitavastatin