期刊
VASCULAR PHARMACOLOGY
卷 46, 期 6, 页码 456-462出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.vph.2007.01.007
关键词
PPAR gamma; rosiglitazone; type 2 diabetes; NADPH oxidase; Cu/Zn superoxide dismutase; superoxide
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.
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