Document Information

PMID 17337254  (  )
Title The PPARgamma ligand, rosiglitazone, reduces vascular oxidative stress and NADPH oxidase expression in diabetic mice.
Abstract 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. Emory University Medical Centers, Decatur, GA 30033, USA.

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Targets by SciMiner Summary

HUGO ID Symbol Target Name #Occur ActualStr
14874NOX5NADPH oxidase, EF-hand calcium binding domain 532nadph oxidase |
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))19SOD |
7891NOX4NADPH oxidase 415Nox-4 |
7889NOX1NADPH oxidase 114nadph oxidase 1 | Nox-1 |
2578CYBBcytochrome b-245, beta polypeptide (chronic granulomatous disease)10Nox-2 | gp91 phox |
13633ADIPOQadiponectin, C1Q and collagen domain containing5adiponectin |
6081INSinsulin5insulin |
6553LEPleptin4leptin |
6554LEPRleptin receptor4leptin receptor |
9232PPARAperoxisome proliferator-activated receptor alpha2PPAR |
7876NOS3nitric oxide synthase 3 (endothelial cell)2endothelial nitric oxide synthase | eNOS |
1516CATcatalase2catalase |
7660NCF1neutrophil cytosolic factor 1, (chronic granulomatous disease, autosomal 1)1p47phox |

 

Targets by SciMiner Full list

HUGO ID Symbol Name ActualStr Score FlankingText
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD4.2NADPH oxidase and increasing Cu/Zn Cu Zn superoxide dismutase (SOD) SOD expression the current study examined the effect of PPAR_amp_#x3b3 ligands
7889NOX1NADPH oxidase 1Nox-12.7_amp_#x2212 generation and mRNA levels of the NADPH oxidase subunits Nox-1 Nox-2 and Nox-4 as well as Nox-4 protein expression were
2578CYBBcytochrome b-245, beta polypeptide (chronic granulomatous disease)Nox-21.5generation and mRNA levels of the NADPH oxidase subunits Nox-1 Nox-2 and Nox-4 as well as Nox-4 protein expression were elevated
7891NOX4NADPH oxidase 4Nox-43.8mRNA levels of the NADPH oxidase subunits Nox-1 Nox-2 and Nox-4 as well as Nox-4 protein expression were elevated in db
7891NOX4NADPH oxidase 4Nox-43.8NADPH oxidase subunits Nox-1 Nox-2 and Nox-4 as well as Nox-4 protein expression were elevated in db _amp_#x2212 /db db _amp_#x2212
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD4.2db /db db _amp_#x2212 mice whereas aortic Cu/Zn Cu Zn SOD protein and PPAR_amp_#x3b3 mRNA levels were reduced in db _amp_#x2212
7889NOX1NADPH oxidase 1Nox-12.7reduced aortic O 2 _amp_#x2212 production and the expression of Nox-1 2 and 4 but failed to increase Cu/Zn Cu Zn
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD4.22 and 4 but failed to increase Cu/Zn Cu Zn SOD or PPAR_amp_#x3b3 in aortic tissue from db _amp_#x2212 /db db
7889NOX1NADPH oxidase 1Nox-12.7These data demonstrate that the vascular expression of Nox-1 2 and 4 subunits of NADPH oxidase is increased in
13633ADIPOQadiponectin, C1Q and collagen domain containingadiponectin1.0Bio-Rad Laboratories Hercules CA in conjunction with kits for leptin adiponectin insulin (Linco Linco Research Inc. St Charles MO triglycerides cholesterol
7889NOX1NADPH oxidase 1Nox-12.7performed to quantify mRNA levels of the NADPH oxidase components Nox-1 Nox-2 (gp91 gp91 phox and Nox-4 as well as PPAR_amp_#x3b3
2578CYBBcytochrome b-245, beta polypeptide (chronic granulomatous disease)Nox-21.5to quantify mRNA levels of the NADPH oxidase components Nox-1 Nox-2 (gp91 gp91 phox and Nox-4 as well as PPAR_amp_#x3b3
7891NOX4NADPH oxidase 4Nox-43.8the NADPH oxidase components Nox-1 Nox-2 (gp91 gp91 phox and Nox-4 as well as PPAR_amp_#x3b3
7889NOX1NADPH oxidase 1Nox-12.7copy numbers were calculated from standard curves generated with mouse Nox-1 Nox-2 Nox-4 PPAR_amp_#x3b3 and 18S templates
2578CYBBcytochrome b-245, beta polypeptide (chronic granulomatous disease)Nox-21.5numbers were calculated from standard curves generated with mouse Nox-1 Nox-2 Nox-4 PPAR_amp_#x3b3 and 18S templates
7891NOX4NADPH oxidase 4Nox-43.8were calculated from standard curves generated with mouse Nox-1 Nox-2 Nox-4 PPAR_amp_#x3b3 and 18S templates
7891NOX4NADPH oxidase 4Nox-43.8Millipore Billerica MA and probed with primary antibodies specific for Nox-4 ( Szocs et al. 2002 (provided provided by Dr David
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD4.2provided by Dr David Lambeth Emory University Cu/Zn Cu Zn SOD (Calbiochem, Calbiochem San Diego CA or actin (Santa Santa Cruz
13633ADIPOQadiponectin, C1Q and collagen domain containingadiponectin1.0_amp_#x2212 mice had similar cholesterol levels but significantly lower serum adiponectin levels than db / db _amp_#x2212 mice ( Table 1
7889NOX1NADPH oxidase 1Nox-12.7aortas from db / db _amp_#x2212 mice mRNA levels of Nox-1 Nox-2 and Nox-4 from db _amp_#x2212 / db _amp_#x2212 mouse
2578CYBBcytochrome b-245, beta polypeptide (chronic granulomatous disease)Nox-21.5from db / db _amp_#x2212 mice mRNA levels of Nox-1 Nox-2 and Nox-4 from db _amp_#x2212 / db _amp_#x2212 mouse aortas
7891NOX4NADPH oxidase 4Nox-43.8/ db _amp_#x2212 mice mRNA levels of Nox-1 Nox-2 and Nox-4 from db _amp_#x2212 / db _amp_#x2212 mouse aortas were increased
7891NOX4NADPH oxidase 4Nox-43.8Nox-4 protein levels in aortic homogenates were examined to confirm the
7891NOX4NADPH oxidase 4Nox-43.8examined to confirm the impact of increased mRNA levels for Nox-4 on gene product abundance
7891NOX4NADPH oxidase 4Nox-43.8Nox-4 protein expression was increased more than 4-fold in db _amp_#x2212
7891NOX4NADPH oxidase 4Nox-43.8to db / db _amp_#x2212 mice and rosiglitazone attenuated increased Nox-4 expression in db _amp_#x2212 / db _amp_#x2212 mice ( Fig
7889NOX1NADPH oxidase 1Nox-12.7Available Nox-1 and Nox-2 antibodies did not permit convincing analysis of rosiglitazone
2578CYBBcytochrome b-245, beta polypeptide (chronic granulomatous disease)Nox-21.5Available Nox-1 and Nox-2 antibodies did not permit convincing analysis of rosiglitazone effects on
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD4.2also investigated changes in the expression of Cu/Zn Cu Zn SOD as an alternative mechanism that could reduce vascular O 2
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD4.2Although Cu/Zn Cu Zn SOD protein expression was significantly reduced in aortas from db _amp_#x2212
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD4.2treatment with rosiglitazone had no effect on Cu/Zn Cu Zn SOD expression suggesting that rosiglitazone effects on NADPH oxidase component expression
13633ADIPOQadiponectin, C1Q and collagen domain containingadiponectin1.0db _amp_#x2212 mice including levels of leptin cholesterol NEFA or adiponectin
7889NOX1NADPH oxidase 1Nox-12.7db _amp_#x2212 mice is associated with increased expression of the Nox-1 2 and 4 subunits of NADPH oxidase a major source
7889NOX1NADPH oxidase 1Nox-12.7knowledge this is the first report to identify elevations of Nox-1 and Nox-4 in db _amp_#x2212 / db _amp_#x2212 mice
7891NOX4NADPH oxidase 4Nox-43.8is the first report to identify elevations of Nox-1 and Nox-4 in db _amp_#x2212 / db _amp_#x2212 mice
7660NCF1neutrophil cytosolic factor 1, (chronic granulomatous disease, autosomal 1)p47phox1.0TZDs can suppress expression of selected NADPH oxidase subunits including p47phox and Nox-2 ( Dobrian et al. 2004 and Tao et
2578CYBBcytochrome b-245, beta polypeptide (chronic granulomatous disease)Nox-21.5suppress expression of selected NADPH oxidase subunits including p47phox and Nox-2 ( Dobrian et al. 2004 and Tao et al. 2003
2578CYBBcytochrome b-245, beta polypeptide (chronic granulomatous disease)Nox-21.5vasorelaxation in hypercholesterolemic rabbits by reducing O 2 _amp_#x2212 and Nox-2 expression ( Tao et al. 2003
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD4.2regulate the rate of O 2 _amp_#x2212 degradation by influencing SOD expression
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD4.2ligands enhanced the expression and activity of Cu/Zn Cu Zn SOD in vascular endothelial cells in vitro ( Hwang et al.
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD4.2in vivo by increasing the expression of Cu/Zn Cu Zn SOD and degradation of O 2 _amp_#x2212 in the vascular wall
9232PPARAperoxisome proliferator-activated receptor alphaPPAR2.2( Calkin et al. 2005 potentially through direct activation of PPAR response elements in the Cu/Zn Cu Zn SOD promoter (
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD4.2activation of PPAR response elements in the Cu/Zn Cu Zn SOD promoter ( Yoo et al. 1999
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD4.2The current study emphasizes however that although Cu/Zn Cu Zn SOD protein expression was reduced in aortas from db _amp_#x2212 /
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD4.2isolated from db _amp_#x2212 / db _amp_#x2212 mice had reduced SOD activity ( Bagi et al. 2004 rosiglitazone treatment for 1-week
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD4.2expression and vascular oxidative stress without increasing Cu/Zn Cu Zn SOD expression
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD4.2oxidase expression and activity rather than enhanced Cu/Zn Cu Zn SOD expression
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD4.2to reducing vascular oxidative stress by increasing Cu/Zn Cu Zn SOD or catalase PPAR_amp_#x3b3 ligands rapidly suppress NADPH oxidase expression and
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD4.2to enhanced NADPH oxidase expression and reduced Cu/Zn Cu Zn SOD expression in db _amp_#x2212 / db _amp_#x2212 mice have not
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD4.2decreased NADPH oxidase subunit expression and increased Cu/Zn Cu Zn SOD expression and activity in vascular endothelial cells in vitro (
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD4.2ligands to suppress NADPH oxidase and enhance Cu/Zn Cu Zn SOD expression in the vascular wall
7889NOX1NADPH oxidase 1Nox-12.7activation in the vascular wall suppresses the enhanced expression of Nox-1 2 and 4 in diabetic animals remains to be defined
7889NOX1NADPH oxidase 1Nox-12.7A preliminary sequence analysis of the promoter elements of Nox-1 2 and 4 does not provide robust evidence for PPAR
9232PPARAperoxisome proliferator-activated receptor alphaPPAR2.2Nox-1 2 and 4 does not provide robust evidence for PPAR response elements that would predict direct regulation of these genes
7876NOS3nitric oxide synthase 3 (endothelial cell)eNOS2.2al. 2003 mediated by TZD-induced alterations in post-translational mechanisms regulating eNOS activity ( Polikandriotis et al. 2005
7889NOX1NADPH oxidase 1Nox-12.7Fig 2._amp_#xa0 The effect of rosiglitazone on aortic Nox-1 Nox-2 Nox-4 and PPAR_amp_#x3b3 mRNA levels
2578CYBBcytochrome b-245, beta polypeptide (chronic granulomatous disease)Nox-21.5Fig 2._amp_#xa0 The effect of rosiglitazone on aortic Nox-1 Nox-2 Nox-4 and PPAR_amp_#x3b3 mRNA levels
7891NOX4NADPH oxidase 4Nox-43.8Fig 2._amp_#xa0 The effect of rosiglitazone on aortic Nox-1 Nox-2 Nox-4 and PPAR_amp_#x3b3 mRNA levels
7889NOX1NADPH oxidase 1Nox-12.7(A) A Nox-1 mRNA (B) B Nox-2 mRNA (C) C Nox-4 mRNA and
2578CYBBcytochrome b-245, beta polypeptide (chronic granulomatous disease)Nox-21.5(A) A Nox-1 mRNA (B) B Nox-2 mRNA (C) C Nox-4 mRNA and (D) D PPAR_amp_#x3b3 mRNA
7891NOX4NADPH oxidase 4Nox-43.8(A) A Nox-1 mRNA (B) B Nox-2 mRNA (C) C Nox-4 mRNA and (D) D PPAR_amp_#x3b3 mRNA
7891NOX4NADPH oxidase 4Nox-43.8Fig 3._amp_#xa0 The effect of rosiglitazone on aortic Nox-4 and Cu/Zn-SOD Cu Zn-SOD protein levels
7891NOX4NADPH oxidase 4Nox-43.8well as representative immunoblots are presented for protein expression of Nox-4 (A) A and Cu/Zn-SOD Cu Zn-SOD (B) B
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0because peroxisome proliferator activated receptor _amp_#x3b3; ppar_amp_#x3b3; ligands reduced superoxide anion o 2 _amp_#x2212; 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_amp_#x3b3; ligands on vascular nadph oxidase and o 2 _amp_#x2212; generation in vivo.
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0 and increasing cu/zn superoxide dismutase sod expression the current study examined the effect of ppar_amp_#x3b3; ligands on vascular nadph oxidase and o 2 _amp_#x2212; generation in vivo.
6554LEPRleptin receptorleptin receptor1.0lean control db + /db _amp_#x2212; and obese diabetic leptin receptor deficient db _amp_#x2212; /db _amp_#x2212; mice were treated with either vehicle or rosiglitazone 3_amp_#xa0;mg/kg/day by gavage for 7 days.
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0aortic o 2 _amp_#x2212; 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 _amp_#x2212; /db _amp_#x2212; compared to db + /db _amp_#x2212; mice whereas aortic cu/zn sod protein and ppar_a
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0these data demonstrate that the vascular expression of nox 1 2 and 4 subunits of nadph oxidase is increased in db _amp_#x2212; /db _amp_#x2212; mice and that short term treatment with the ppar_amp_#x3b3; agonist rosiglitazone has the potential to rapidly suppress vascular nadph oxidase express
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0 is increased in db _amp_#x2212; /db _amp_#x2212; mice and that short term treatment with the ppar_amp_#x3b3; agonist rosiglitazone has the potential to rapidly suppress vascular nadph oxidase expression and o 2 _amp_#x2212; production through mechanisms that do not appear to depend on correction of diabetic metabolic derangements.
6081INSinsulininsulin1.0the peroxisome proliferator activated receptor _amp_#x3b3; ppar_amp_#x3b3; constitutes the molecular target of thiazolidinediones tzd a class of insulin sensitizing drugs that includes rosiglitazone pioglitazone and troglitazone employed in the treatment of t2dm.
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0for example ppar_amp_#x3b3; activation reduced o 2 _amp_#x2212; generation and nadph oxidase expression in vascular endothelial cells in vitro hwang et al. 2005 and increased no production calnek et al. 2003 through ppar_amp_#x3b3; dependent mechanisms polikandriotis et al. 2005 .
6554LEPRleptin receptorleptin receptor1.0the leptin receptor deficient mouse c57bl/ksj db _amp_#x2212; / db _amp_#x2212; has a mutation on chromosome 4 that inhibits the expression of leptin receptors rendering homozygous db _amp_#x2212; / db _amp_#x2212; mice
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0the current study demonstrates that aortic o 2 _amp_#x2212; generation and the expression of specific nadph oxidase subunits are increased in this animal model and that short term treatment with rosiglitazone reduced vascular o 2 _amp_#x2212; production by suppressing nadph oxidase subunit expression.
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0 subunits are increased in this animal model and that short term treatment with rosiglitazone reduced vascular o 2 _amp_#x2212; production by suppressing nadph oxidase subunit expression.
6554LEPRleptin receptorleptin receptor1.0all studies were performed on 12_amp_#xa0;week old male wild type c57bl/ksj db + / db _amp_#x2212; or diabetic leptin receptor deficient c57bl/ksj db _amp_#x2212; / db _amp_#x2212; mice jackson laboratory bar harbor me .
6081INSinsulininsulin1.0serum from animals was assayed using a multiplex optical bead analyzer bio rad laboratories hercules ca in conjunction with kits for leptin adiponectin insulin linco research inc. st charles mo triglycerides cholesterol roche diagnostics corporation indianapolis in and non esterified fatty acids waco pure chemicals osaka japan . 2.3.
6553LEPleptinleptin1.0serum from animals was assayed using a multiplex optical bead analyzer bio rad laboratories hercules ca in conjunction with kits for leptin adiponectin insulin linco research inc. st charles mo triglycerides cholesterol roche diagnostics corporation indianapolis in and non esterified fatty acids waco pure chemicals osaka japan . 2.3.
13633ADIPOQadiponectin, C1Q and collagen domain containingadiponectin1.0serum from animals was assayed using a multiplex optical bead analyzer bio rad laboratories hercules ca in conjunction with kits for leptin adiponectin insulin linco research inc. st charles mo triglycerides cholesterol roche diagnostics corporation indianapolis in and non esterified fatty acids waco pure chemicals osaka japan . 2.3.
2578CYBBcytochrome b-245, beta polypeptide (chronic granulomatous disease)gp91 phox1.0real time pcr was performed to quantify mrna levels of the nadph oxidase components nox 1 nox 2 gp91 phox and nox 4 as well as ppar_amp_#x3b3;.
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0real time pcr was performed to quantify mrna levels of the nadph oxidase components nox 1 nox 2 gp91 phox and nox 4 as well as ppar_amp_#x3b3;.
6081INSinsulininsulin1.0as illustrated in table 1 at 13_amp_#xa0;weeks of age db _amp_#x2212; / db _amp_#x2212; mice weighed more and demonstrated derangements in serum metabolic markers such as glucose insulin leptin triglycerides tg and non esterified fatty acids nefa compared with age matched lean controls db + / db _amp_#x2212; .
6553LEPleptinleptin1.0as illustrated in table 1 at 13_amp_#xa0;weeks of age db _amp_#x2212; / db _amp_#x2212; mice weighed more and demonstrated derangements in serum metabolic markers such as glucose insulin leptin triglycerides tg and non esterified fatty acids nefa compared with age matched lean controls db + / db _amp_#x2212; .
13633ADIPOQadiponectin, C1Q and collagen domain containingadiponectin1.0in contrast db _amp_#x2212; / db _amp_#x2212; mice had similar cholesterol levels but significantly lower serum adiponectin levels than db + / db _amp_#x2212; mice table 1 .
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0nadph oxidase is an important source of vascular o 2 _amp_#x2212; generation hwang et al. 2003 .
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0to determine the potential role of nadph oxidase in vascular oxidative stress in db _amp_#x2212; / db _amp_#x2212; mice we examined the mrna levels of nox homologues in control and obese mice.
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0these membrane components of nadph oxidase are expressed in the vascular system sorescu et al. 2002 and to our knowledge the impact of ppar_amp_#x3b3; activation on the expression of these components has not been previously examined in this m
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0 was significantly reduced in aortas from db _amp_#x2212; / db _amp_#x2212; mice short term treatment with rosiglitazone had no effect on cu/zn sod expression suggesting that rosiglitazone effects on nadph oxidase component expression constitute a more plausible mechanism for rosiglitazone mediated reductions in aortic o 2 _amp_#x2212; generation fig 3 . 4.
6554LEPRleptin receptorleptin receptor1.0the current study examined vascular oxidative stress and nadph oxidase expression in the leptin receptor deficient obese db _amp_#x2212; / db _amp_#x2212; mouse model of t2dm.
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0the current study examined vascular oxidative stress and nadph oxidase expression in the leptin receptor deficient obese db _amp_#x2212; / db _amp_#x2212; mouse model of t2dm.
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0our studies extend these reports: 1 by defining specific nadph oxidase subunits that are upregulated in diabetic rodent vasculature and 2 by demonstrating that short term treatment with rosiglitazone can rapidly attenuate vascular nadph oxidase and oxidative stress in d
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0 subunits that are upregulated in diabetic rodent vasculature and 2 by demonstrating that short term treatment with rosiglitazone can rapidly attenuate vascular nadph oxidase and oxidative stress in diabetes in vivo .
6081INSinsulininsulin1.0t2dm is frequently associated with elevated systemic blood pressure obesity insulin resistance hyperinsulinemia hyperglycemia and impaired endothelium dependent arteriolar vasodilation bagi et al. 2004 bagi et al. 2003 erdos et al. 2002 and pannirselvam et al. 2002 .
6081INSinsulininsulin1.0as previously reported bagi et al. 2004 rosiglitazone treatment for 1 week failed to affect body weight or serum glucose or insulin levels in db _amp_#x2212; / db _amp_#x2212; mice table 1 .
6553LEPleptinleptin1.0e findings to demonstrate that 1 week of rosiglitazone therapy also failed to reduce derangements in other important metabolic parameters in db _amp_#x2212; / db _amp_#x2212; mice including levels of leptin cholesterol nefa or adiponectin.
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0the current study extends their findings to clarify that vascular oxidative stress in db _amp_#x2212; / db _amp_#x2212; mice is associated with increased expression of the nox 1 2 and 4 subunits of nadph oxidase a major source of o 2 _amp_#x2212; generation in the vascular wall hwang et al. 2005 and hwang et al. 2003 .
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0our findings also demonstrate that short term rosiglitazone therapy attenuates enhanced expression of these nadph oxidase subunits.
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0previous studies have shown that tzds can suppress expression of selected nadph oxidase subunits including p47phox and nox 2 dobrian et al. 2004 and tao et al. 2003 .
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0coupled with evidence that ppar_amp_#x3b3; ligands suppress nox homolog expression in vascular endothelial cells in vitro hwang et al. 2005 these results indicate that nadph oxidase constitutes an important target of ppar_amp_#x3b3; signaling in the vascular wall that is independent of the metabolic effects of ppar_amp_#x3b3; ligands.
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0in addition to regulating vascular o 2 _amp_#x2212; generation by altering the expression of o 2 _amp_#x2212; producing enzymes like nadph oxidase ppar_amp_#x3b3; could regulate the rate of o 2 _amp_#x2212; degradation by influencing sod expression.
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0for example in addition to suppressing nadph oxidase expression ppar_amp_#x3b3; ligands enhanced the expression and activity of cu/zn sod in vascular endothelial cells in vitro hwang et al. 2005 .
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0onsistent with a previous report that aortas isolated from db _amp_#x2212; / db _amp_#x2212; mice had reduced sod activity bagi et al. 2004 rosiglitazone treatment for 1 week was sufficient to reduce nadph oxidase expression and vascular oxidative stress without increasing cu/zn sod expression.
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0based on these findings we speculate that the reduction in vascular o 2 _amp_#x2212; generation caused by treatment with rosiglitazone for 1 week fig 1 is attributable to reduced nadph oxidase expression and activity rather than enhanced cu/zn sod expression.
1516CATcatalasecatalase1.0rosiglitazone may also reduce vascular oxidative stress by enhancing catalase expression and activity bagi et al. 2004 .
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0thus our findings demonstrate that in addition to reducing vascular oxidative stress by increasing cu/zn sod or catalase ppar_amp_#x3b3; ligands rapidly suppress nadph oxidase expression and activity providing additional insights into previous reports that tzds restore endothelial function bagi et al. 2004 and majithiya et al. 2005 .
1516CATcatalasecatalase1.0thus our findings demonstrate that in addition to reducing vascular oxidative stress by increasing cu/zn sod or catalase ppar_amp_#x3b3; ligands rapidly suppress nadph oxidase expression and activity providing additional insights into previous reports that tzds restore endothelial function bagi et al. 2004 and majithiy
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0the mechanisms leading to enhanced nadph oxidase expression and reduced cu/zn sod expression in db _amp_#x2212; / db _amp_#x2212; mice have not been defined.
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0based on evidence that ppar_amp_#x3b3; ligands decreased nadph oxidase subunit expression and increased cu/zn sod expression and activity in vascular endothelial cells in vitro hwang et al. 2005 we questioned if ppar_amp_#x3b3; expression might be reduced in db _amp_#x2
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0hwang et al. 2005 we questioned if ppar_amp_#x3b3; expression might be reduced in db _amp_#x2212; / db _amp_#x2212; mice thereby reducing the ability of endogenous ppar_amp_#x3b3; ligands to suppress nadph oxidase and enhance cu/zn sod expression in the vascular wall.
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0he level of ppar_amp_#x3b3; expression in the aortas of db _amp_#x2212; / db _amp_#x2212; mice was sufficient to permit significant rosiglitazone induced reductions in o 2 _amp_#x2212; generation and nadph oxidase expression as reported in fig. 1 fig. 2 and fig. 3 .
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0postulate that the previously reported ability of ppar_amp_#x3b3; ligands to suppress the activity of pro inflammatory transcription factors may contribute to the ability of rosiglitazone to suppress nadph oxidase subunit expression jiang et al. 1998 pascual et al. 2005 and ricote et al. 1998 .
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0our results clarify that mechanisms of tzd induced vascular protection include suppression of specific nadph oxidase subunit expression and aortic superoxide production similar to previously reported direct effects of ppar_amp_#x3b3; ligands on vascular endothelial cells in vitro hwang et al. 2005 .
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0the mechanisms of ppar_amp_#x3b3; induced suppression of nadph oxidase subunits remain to be defined and constitute an area of active investigation in our lab.
7876NOS3nitric oxide synthase 3 (endothelial cell)endothelial nitric oxide synthase1.0function caused by sustained ppar_amp_#x3b3; activation in t2dm as well as in other disorders associated with endothelial dysfunction may be related to direct effects of ppar_amp_#x3b3; activation on endothelial nitric oxide synthase activity calnek et al. 2003 mediated by tzd induced alterations in post translational mechanisms regulating enos activity polikandriotis et al. 2005 .
6553LEPleptinleptin1.0hypoglycemic agents|membrane glycoproteins|ppar gamma|rna messenger|receptors cell surface|receptors leptin|thiazolidinediones|superoxides|rosiglitazone|nadh nadph oxidoreductases|nox4 protein mouse|cybb protein mouse|nadph oxidase|nadph oxidase 1|
7889NOX1NADPH oxidase 1nadph oxidase 11.0coproteins|ppar gamma|rna messenger|receptors cell surface|receptors leptin|thiazolidinediones|superoxides|rosiglitazone|nadh nadph oxidoreductases|nox4 protein mouse|cybb protein mouse|nadph oxidase|nadph oxidase 1|