The PPARγ ligand, rosiglitazone, reduces vascular oxidative stress and NADPH oxidase expression in diabetic mice

Oxidative stress plays an important role in diabetic vascular dysfunction. The sources and regulation of reactive oxygen species production in diabetic vasculature continue to be defined. Because peroxisome proliferator-activated receptor gamma (PPAR gamma) ligands reduced superoxide anion (O-2(-center dot) generation in vascular endothelial cells in vitro by reducing NADPH oxidase and increasing Cu/Zn superoxide dismutase (SOD) expression, the current study examined the effect of PPAR gamma ligands on vascular NADPH oxidase and O-2(-center dot) generation in vivo. Lean control (db(+)/db(-)) and obese, diabetic, leptin receptor-deficient (db(-)/db(-)) mice were treated with either vehicle or rosiglitazone (3 mg/kg/day) by gavage for 7days. Compared to controls, db(-)/db(-) mice weighed more and had metabolic derangements that were not corrected by treatment with rosiglitazone for 1-week. Aortic O-2(-center dot) generation and mRNA levels of the NADPH oxidase subunits, Nox-1, Nox-2, and Nox-4 as well as Nox-4 protein expression were elevated in db(-)/db(-) compared to db(+)/db(-) mice, whereas aortic Cu/Zn SOD protein and PPAR gamma mRNA levels were reduced in db(-)/db(-) mice. Treatment with rosiglitazone for 1-week significantly reduced aortic O-2(-center dot) production and the expression of Nox-1, 2, and 4 but failed to increase Cu/Zn SOD or PPAR gamma in aortic tissue from db(-)/db(-) mice. These data demonstrate that the vascular expression of Nox-1, 2, and 4 subunits of NADPH oxidase is increased in db(-)/db(-) mice and that short-term treatment with the PPAR gamma agonist, rosiglitazone, has the potential to rapidly suppress vascular NADPH oxidase expression and O-2(-center dot) production through mechanisms that do not appear to depend on correction of diabetic metabolic derangements. (c) 2007 Elsevier Inc. All rights reserved.