ucn-1028-c and pitavastatin

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.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Cattle; Cells, Cultured; Deoxyguanosine; Diabetes Mellitus, Experimental; Electron Spin Resonance Spectroscopy; Endothelial Cells; Endothelium, Vascular; Glucose; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Naphthalenes; Oxidative Stress; Protein Kinase C; Quinolines; rac1 GTP-Binding Protein; Rats