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 γ (PPARγ) ligands reduced superoxide anion (O2−) 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 PPARγ ligands on vascular NADPH oxidase and O2− 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 7-days. Compared to controls, db−/db− mice weighed more and had metabolic derangements that were not corrected by treatment with rosiglitazone for 1-week. Aortic O2− 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 PPARγ mRNA levels were reduced in db−/db− mice. Treatment with rosiglitazone for 1-week significantly reduced aortic O2− production and the expression of Nox-1, 2, and 4 but failed to increase Cu/Zn SOD or PPARγ 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 PPARγ agonist, rosiglitazone, has the potential to rapidly suppress vascular NADPH oxidase expression and O2− production through mechanisms that do not appear to depend on correction of diabetic metabolic derangements.