The PPARgamma 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 (PPARgamma) ligands reduced superoxide anion (O(2)(-.)) 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 PPARgamma ligands on vascular NADPH oxidase and O(2)(-.) 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 O(2)(-.) 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 PPARgamma mRNA levels were reduced in db(-)/db(-) mice. Treatment with rosiglitazone for 1-week significantly reduced aortic O(2)(-.) production and the expression of Nox-1, 2, and 4 but failed to increase Cu/Zn SOD or PPARgamma 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 PPARgamma agonist, rosiglitazone, has the potential to rapidly suppress vascular NADPH oxidase expression and O(2)(-.) production through mechanisms that do not appear to depend on correction of diabetic metabolic derangements.
Hwang
Jinah
J
Division of Pulmonary and Critical Care Medicine, Veterans Affairs and Emory University Medical Centers, Decatur, GA 30033, USA.
Kleinhenz
Dean J
DJ
Rupnow
Heidi L
HL
Campbell
Adam G
AG
Thulé
Peter M
PM
Sutliff
Roy L
RL
Hart
C Michael
CM
D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000201:enzymology; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D000074624:NADPH Oxidase 1; D000074662:NADPH Oxidase 2; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D047495:PPAR gamma / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D054411:Receptors, Leptin; D000077154:Rosiglitazone; D013481:Superoxides / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology* / Q000627:therapeutic use
D007004:Hypoglycemic Agents; D008562:Membrane Glycoproteins; D047495:PPAR gamma; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D013481:Superoxides; D009247:NADH, NADPH Oxidoreductases; C488842:Cybb protein, mouse; D000074624:NADPH Oxidase 1; D000074662:NADPH Oxidase 2; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse