Abstract 33: Atorvastatin Downregulates Vascular Nox Expression and Ameliorates Oxidative Stress-associated Inflammatory Process in Type 2 Diabetic Db/db Mice

Abstract

Nox-derived reactive oxygen species generation plays a role in endothelial dysfunction and vascular inflammation, which underline vascular damage observed in diabetes. Increasing evidence indicates that the beneficial effects of atorvastatin are associated with antioxidant mechanisms. We tested the hypothesis that atorvastatin influences Nox isoforms expression and ameliorates diabetes-associated vascular inflammation and redox signalling. Diabetic mice (db/db model of obesity and diabetes type II) and their control counterparts (db/+) were treated with atorvastatin (10 mg/Kg/day, p.o., 2 weeks). No differences were observed in BP among the groups. Improved oral glucose tolerance was observed in atorvastatin-treated db/db group (area under curve, db/db: 2858 ± 81 vs db/db atorvastatin: 2251 ± 158). Atorvastatin lowered plasma thiobarbituric acid-reacting substances levels in db/db mice (db/+: 4,7 ± 0,7 ;db/db: 6,5 ± 1,1 vs db/db atorvastatin: 4,9 ± 0,5 ). Increased expression of Nox1, 2 and 4 (1 to 3 fold increase vs db/+) and the associated enhance of ROS generation in the vasculature of db/db mice (db/+: 4312 ± 874; db/db: 27828 ± 8215 vs db/db atorvastatin: 8742 ± 2393 RLU) were abrogated by atorvastatin. The increase of vascular p47phox and RAC1/2 membrane translocation observed in db/db mice was also inhibited by atorvastatin. Diabetes-associated increase of VCAM-1 expression, NFkB p65 phosphorylation, and vascular monocyte adhesion were reduced by aotrvastatin treatment. Higher MAP kinase phophorylation levels observed in db/db mice were blunted by atorvastatin. Impaired vascular responses to acetylcholine (maxium effect %; db/+: 83 ± 5,1 ;db/db: 48 ± 6,4 vs db/db atorvastatin: 75 ± 5,2) and insulin (maxium effect %; db/+: 103 ± 7,5 ;db/db: 47 ± 2,0 vs db/db atorvastatin: 95 ± 7,1) in db/db mice were normalized by atorvastatin treatment. Our results demontrate that atorvastatin ameliorates oxidative stress and inflammatory process in db/db mice. Findings from this study identify NADPH oxidase as a target for atorvastatin. We describe novel mechanisms whereby statins may improve vascular function in obesity-associated diabetes.