Vascular injury in diabetic db/db mice is ameliorated by atorvastatin: Role of Rac1/2-sensitive Nox-dependent pathways

Oxidative stress [increased bioavailaibility of reactive oxygen species (ROS)] plays a role in endothelial dysfunction and vascular inflammation, which underlie vascular damage in diabetes. Statins are cholesterol-lowering drugs that are vasoprotective in diabetes through unknown mechanisms. We tested the hypothesis that atorvastatin decreases NADPH oxidase (Nox)-derived ROS generation and associated vascular injury in diabetes. Leprdb/Leprdb (db/db) mice, a model of type 2 diabetes, and control Leprdb/Lepr+ (db/+) mice were administered atorvastatin (10 mg/kg/day, 2 weeks). Atorvastatin improved glucose tolerance in db/db mice. Systemic and vascular oxidative stress in db/db mice, characterized by increased plasma TBARS levels and exaggerated vascular Nox-derived ROS generation respectively, were inhibited by atorvastatin. Cytosol-to-membrane translocation of the NADPH oxidase regulatory subunit p47phox and the small GTPase Rac1/2 was increased in vessels from db/db mice compared with db/+, an effect blunted by atorvastatin. The increase of vascular Nox1/2/4 expression and increased phosphorylation of redox-sensitive MAPKs was abrogated by atorvastatin in db/db mice. Pro-inflammatory signaling (decreased IκB-α and increased NFκBp50 expression, increased NFκBp65 phosphorylation) and associated vascular inflammation (VCAM-1 expression and vascular monocyte adhesion), which were increased in aortas of db/db mice, were blunted by ...

Source: Clinical Science - October 31, 2014 Category: Biomedical Science Authors: T Bruder-Nascimento, G E Callera, A C Montezano, Y He, T T Antunes, A Nguyen Dinh Cat, R C Tostes R, R M Touyz Source Type: research