Document Information

PMID 15993337  (  )
Title Differential effects of diabetes on the expression of the gp91phox homologues nox1 and nox4.
Abstract The nox2-dependent NADPH oxidase was shown to be a major superoxide source in vascular disease, including diabetes. Smooth muscle cells of large arteries lack the phagocytic gp91phox subunit of the enzyme; however, two homologues have been identified in these cells, nox1 and nox4. It remained to be established whether also increases in protein levels of the nonphagocytic NADPH oxidase contribute to increased superoxide formation in diabetic vessels. To investigate changes in the expression of these homologues, we measured their expression in aortic vessels of type I diabetic rats. Eight weeks after streptozotocin treatment, we found a doubling in nox1 protein expression, while the expression of nox4 remained unchanged. This was associated with a significant increase in the NADPH oxidase activity in membrane fractions of diabetic heart and aortic tissue. Furthermore, we observed a decreased sensitivity of diabetic vessels to acetylcholine and nitroglycerin and a decrease in both acetylcholine-stimulated NO production and phosphorylation of VASP, despite an increase in endothelial NO synthase (NOSIII) expression. In addition, xanthine oxidase activity was markedly increased in plasma and 100,000 g supernatant of cardiac tissue of diabetic rats, while myocardial mitochondrial superoxide formation was only weakly enhanced. We conclude that in addition to phagocytic NADPH oxidase, also nonphagocytic, vascular NADPH oxidase subunit nox1, uncoupled NOSIII, and plasma xanthine oxidase contribute to endothelial dysfunction in the setting of diabetes mellitus. Germany.

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Targets by SciMiner Summary

HUGO ID Symbol Target Name #Occur ActualStr
7891NOX4NADPH oxidase 438nox4 | NOX4 |
7889NOX1NADPH oxidase 130nadph oxidase 1 | Nox1 | nox1 |
14874NOX5NADPH oxidase, EF-hand calcium binding domain 528nadph oxidase |
12805XDHxanthine dehydrogenase21xanthine oxidase |
2578CYBBcytochrome b-245, beta polypeptide (chronic granulomatous disease)20nox2 | gp91 phox | nox2-dependent |
2707ACEangiotensin I converting enzyme (peptidyl-dipeptidase A) 19ACE |
2577CYBAcytochrome b-245, alpha polypeptide8p22 phox |
7660NCF1neutrophil cytosolic factor 1, (chronic granulomatous disease, autosomal 1)5p47 |
333AGTangiotensinogen (serpin peptidase inhibitor, clade A, member 8)4angiotensin ii |
7661NCF2neutrophil cytosolic factor 2 (65kDa, chronic granulomatous disease, autosomal 2)3p67 phox |
9414PRKG1protein kinase, cGMP-dependent, type I3cGK-I |
12652VASPvasodilator-stimulated phosphoprotein2VASP |
19986CYCScytochrome c, somatic2cytochrome c |
7872NOS1nitric oxide synthase 1 (neuronal)2NOS |
7873NOS2Anitric oxide synthase 2A (inducible, hepatocytes)1nitric oxide synthase |
8800PDGFBplatelet-derived growth factor beta polypeptide (simian sarcoma viral (v-sis) oncogene homolog)1platelet derived growth factor |
6081INSinsulin1insulin |
9958RENrenin1renin |
336AGTR1angiotensin II receptor, type 11angiotensin ii receptor |
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))1superoxide dismutase |

 

Targets by SciMiner Full list

HUGO ID Symbol Name ActualStr Score FlankingText
2578CYBBcytochrome b-245, beta polypeptide (chronic granulomatous disease)nox2-dependent2.3The nox2-dependent NADPH oxidase was shown to be a major superoxide source
7889NOX1NADPH oxidase 1nox13.2enzyme however two homologues have been identified in these cells nox1 and nox4
7891NOX4NADPH oxidase 4NOX41.9enzyme however two homologues have been identified in these cells nox1 and nox4
7891NOX4NADPH oxidase 4nox41.9two homologues have been identified in these cells nox1 and nox4
7889NOX1NADPH oxidase 1nox13.2Eight weeks after streptozotocin treatment we found a doubling in nox1 protein expression while the expression of nox4 remained unchanged
7891NOX4NADPH oxidase 4nox41.9a doubling in nox1 protein expression while the expression of nox4 remained unchanged
12652VASPvasodilator-stimulated phosphoproteinVASP1.6a decrease in both acetylcholine-stimulated NO production and phosphorylation of VASP despite an increase in endothelial NO synthase (NOSIII) NOSIII expression
7889NOX1NADPH oxidase 1nox13.2to phagocytic NADPH oxidase also nonphagocytic vascular NADPH oxidase subunit nox1 uncoupled NOSIII and plasma xanthine oxidase contribute to endothelial dysfunction
7872NOS1nitric oxide synthase 1 (neuronal)NOS1.2toward NADPH oxidase and an uncoupled nitric oxide synthase (NOS) NOS 3 as potential superoxide sources
7660NCF1neutrophil cytosolic factor 1, (chronic granulomatous disease, autosomal 1)p470.9phox and p22 phox as well as the cytosolic factors p47 phox and p67 phox and the small molecular weight G
2577CYBAcytochrome b-245, alpha polypeptidep220.0consist of the flavocytochrome b 558 subunits gp91 phox and p22 phox as well as the cytosolic factors p47 phox and
7660NCF1neutrophil cytosolic factor 1, (chronic granulomatous disease, autosomal 1)p470.9Furthermore p47 phox protein was increased in rat ventricular myocytes cultured in
7889NOX1NADPH oxidase 1nox13.2phox but instead express the recently identified gp91 phox homologues nox1 and nox4 12 and 13
7891NOX4NADPH oxidase 4NOX41.9phox but instead express the recently identified gp91 phox homologues nox1 and nox4 12 and 13
7891NOX4NADPH oxidase 4nox41.9instead express the recently identified gp91 phox homologues nox1 and nox4 12 and 13
7889NOX1NADPH oxidase 1nox13.2Both nox1 and nox4 mRNA were also detected in endothelial cells and
7891NOX4NADPH oxidase 4NOX41.9Both nox1 and nox4 mRNA were also detected in endothelial cells and
7891NOX4NADPH oxidase 4nox41.9Both nox1 and nox4 mRNA were also detected in endothelial cells and fibroblasts whereas
2578CYBBcytochrome b-245, beta polypeptide (chronic granulomatous disease)nox22.8in endothelial cells and fibroblasts whereas a high level of nox2 mRNA much less nox1 and no nox4 was detectable in
7889NOX1NADPH oxidase 1nox13.2fibroblasts whereas a high level of nox2 mRNA much less nox1 and no nox4 was detectable in inflammatory cells 14
7891NOX4NADPH oxidase 4nox41.9high level of nox2 mRNA much less nox1 and no nox4 was detectable in inflammatory cells 14
7889NOX1NADPH oxidase 1nox13.2Overexpression of nox1 in fibroblasts and nox4 expression in the kidney increased superoxide
7891NOX4NADPH oxidase 4nox41.9Overexpression of nox1 in fibroblasts and nox4 expression in the kidney increased superoxide production 12 and 15
7891NOX4NADPH oxidase 4nox41.9in the kidney increased superoxide production 12 and 15 while nox4 overexpression in adipose cells increased insulin-induced hydrogen peroxide production 16
7660NCF1neutrophil cytosolic factor 1, (chronic granulomatous disease, autosomal 1)p470.9and/or and or protein levels of gp91 phox p22 phox p47 phox and p67 phox in blood vessels from diabetic animals
2577CYBAcytochrome b-245, alpha polypeptidep220.0increased mRNA and/or and or protein levels of gp91 phox p22 phox p47 phox and p67 phox in blood vessels from
7889NOX1NADPH oxidase 1nox13.2Gp91 phox nox1 and nox4 harbor the electron-transfer moieties of the enzyme complex
7891NOX4NADPH oxidase 4NOX41.9Gp91 phox nox1 and nox4 harbor the electron-transfer moieties of the enzyme complex
7891NOX4NADPH oxidase 4nox41.9Gp91 phox nox1 and nox4 harbor the electron-transfer moieties of the enzyme complex and thus
2578CYBBcytochrome b-245, beta polypeptide (chronic granulomatous disease)nox22.8our group 1 and others 17 on the role of nox2 (gp91 gp91 phox in diabetes the effect of streptozotocin-induced type
7889NOX1NADPH oxidase 1nox13.2I diabetes on the expression of the NADPH oxidase subunits nox1 and nox4 and on the vascular NADPH oxidase activity was
7891NOX4NADPH oxidase 4NOX41.9I diabetes on the expression of the NADPH oxidase subunits nox1 and nox4 and on the vascular NADPH oxidase activity was
7891NOX4NADPH oxidase 4nox41.9on the expression of the NADPH oxidase subunits nox1 and nox4 and on the vascular NADPH oxidase activity was analyzed
7889NOX1NADPH oxidase 1nox13.2monoclonal anti-eNOS antibody was from Transduction Laboratories (Heidelberg, Heidelberg Germany nox1 antibody from Santa Cruz Biotechnology (CA), CA anti-VASP phospho-specific and
2707ACEangiotensin I converting enzyme (peptidyl-dipeptidase A) 1ACE0.3Measurement of ACE activity of serum
2707ACEangiotensin I converting enzyme (peptidyl-dipeptidase A) 1ACE0.3Serum samples were prepared and the ACE activity was determined spectrophotometrically by the Department of Clinical Chemistry
7889NOX1NADPH oxidase 1nox13.2antibody against NOSIII (1:1000), 1 1000 a polyclonal antibody against nox1 (1:100), 1 100 a polyclonal antibody against nox4 (1:1000), 1
7891NOX4NADPH oxidase 4nox41.9antibody against nox1 (1:100), 1 100 a polyclonal antibody against nox4 (1:1000), 1 1000 a monclonal antibody against phospho-specifc vasodilator-stimulated phophoprotein
9414PRKG1protein kinase, cGMP-dependent, type IcGK-I1.21 1 2500 and against cGMP-dependent protein kinase I (cGK-I; cGK-I 1 1000
7891NOX4NADPH oxidase 4nox41.9The nox4 antibody was produced by immunizing rabbits with a synthetic peptide
7891NOX4NADPH oxidase 4nox41.9a synthetic peptide corresponding to residues 140_amp_#x2013 153 of human nox4 and the antibody was affinity-purified as described previously 23
2707ACEangiotensin I converting enzyme (peptidyl-dipeptidase A) 1ACE0.3ACE activity of serum
2707ACEangiotensin I converting enzyme (peptidyl-dipeptidase A) 1ACE0.3Because of the observed positive effects of ACE inhibitors and angiotensin II receptor blockade the renin/angiotensin renin angiotensin
2707ACEangiotensin I converting enzyme (peptidyl-dipeptidase A) 1ACE0.3Therefore we measured the ACE activity in serum of control and diabetic animals
2707ACEangiotensin I converting enzyme (peptidyl-dipeptidase A) 1ACE0.3ACE activity was significantly increased in the diabetic animals as compared
7889NOX1NADPH oxidase 1nox13.2Effect of STZ treatment on the protein expression of nox1 nox4 and constituents of the NO/cGMP NO cGMP signaling pathway
7891NOX4NADPH oxidase 4nox41.9Effect of STZ treatment on the protein expression of nox1 nox4 and constituents of the NO/cGMP NO cGMP signaling pathway
7889NOX1NADPH oxidase 1nox13.2and control aortas by Western blotting using specific antibodies for nox1 and nox4
7891NOX4NADPH oxidase 4NOX41.9and control aortas by Western blotting using specific antibodies for nox1 and nox4
7891NOX4NADPH oxidase 4nox41.9aortas by Western blotting using specific antibodies for nox1 and nox4
7889NOX1NADPH oxidase 1nox13.2migrating with an apparent molecular weight of 65 kDa (nox1) nox1 and 70 kDa (nox4) nox4 ( Fig 4
7891NOX4NADPH oxidase 4nox41.9weight of 65 kDa (nox1) nox1 and 70 kDa (nox4) nox4 ( Fig 4
7891NOX4NADPH oxidase 4nox41.9Preincubation of the nox4 primary antibody with the respective peptide used for immunization of
7889NOX1NADPH oxidase 1nox13.2In aorta of diabetic animals the expression of nox1 was increased by 2-fold compared to nondiabetic rats ( Fig
7891NOX4NADPH oxidase 4nox41.9to nondiabetic rats ( Fig 4 while the expression of nox4 was not different between diabetic and control animals
9414PRKG1protein kinase, cGMP-dependent, type IcGK-I1.2we further analyzed the expression of NOSIII sGC_amp_#x3b2 1 and cGK-I by Western blotting
9414PRKG1protein kinase, cGMP-dependent, type IcGK-I1.2contrast the expression of sGC_amp_#x3b2 1 (70 70 kDa and cGK-I (75 75 kDa was not significantly affected by diabetes (data
12652VASPvasodilator-stimulated phosphoproteinVASP1.6The phosphorylation state of VASP at serine 239 (Ser Ser 239 -P-VASP is a reliable
7889NOX1NADPH oxidase 1nox13.2the first evidence for upregulation of the gp91 phox homologue nox1 in the aorta from type I diabetic animals
7889NOX1NADPH oxidase 1nox13.2the vessel wall as well as the expression of the nox1 but not nox4
7891NOX4NADPH oxidase 4nox41.9as well as the expression of the nox1 but not nox4
7889NOX1NADPH oxidase 1nox13.2Increased expression of nox1 was associated with an increase in NADPH oxidase activity in
7872NOS1nitric oxide synthase 1 (neuronal)NOS1.2despite a small but significant increase in the expression of NOS III possibly pointing to an uncoupled NOSIII as recently observed
2578CYBBcytochrome b-245, beta polypeptide (chronic granulomatous disease)nox22.8As shown previously also nox2 1 and 17 mitochondria 4 and 5 and xanthine oxidase
7660NCF1neutrophil cytosolic factor 1, (chronic granulomatous disease, autosomal 1)p470.9oxidase subunits p22 phox and gp91 phox as well as p47 phox and p67 phox at the mRNA and protein level
2577CYBAcytochrome b-245, alpha polypeptidep220.0as well as increased expression of the NADPH oxidase subunits p22 phox and gp91 phox as well as p47 phox and
7660NCF1neutrophil cytosolic factor 1, (chronic granulomatous disease, autosomal 1)p470.9increased levels of the NADPH oxidase subunits p22 phox and p47 phox colocalized with macrophages 32
2577CYBAcytochrome b-245, alpha polypeptidep220.0from atherosclerotic monkeys increased levels of the NADPH oxidase subunits p22 phox and p47 phox colocalized with macrophages 32
7889NOX1NADPH oxidase 1nox13.2large arteries lack gp91 phox but instead express the homologues nox1 and nox4
7891NOX4NADPH oxidase 4NOX41.9large arteries lack gp91 phox but instead express the homologues nox1 and nox4
7891NOX4NADPH oxidase 4nox41.9lack gp91 phox but instead express the homologues nox1 and nox4
7891NOX4NADPH oxidase 4nox41.9Normally the expression of nox4 is about 150 times higher than that of nox1 33
7889NOX1NADPH oxidase 1nox13.2of nox4 is about 150 times higher than that of nox1 33
7889NOX1NADPH oxidase 1nox13.2infusion 34 as well as carotid injury 33 drastically increases nox1 expression with no or minor change in nox4 expression
7891NOX4NADPH oxidase 4nox41.9drastically increases nox1 expression with no or minor change in nox4 expression
7889NOX1NADPH oxidase 1nox13.2While nox1 mediates agonist-induced superoxide production and proliferation of smooth muscle cells
7891NOX4NADPH oxidase 4nox41.9agonist-induced superoxide production and proliferation of smooth muscle cells 35 nox4 may be more involved in steady-state production of low amounts
7889NOX1NADPH oxidase 1nox13.2was associated with a 2-fold increase in the expression of nox1 protein in aorta of diabetic animals while nox4 expression remained
7891NOX4NADPH oxidase 4nox41.9expression of nox1 protein in aorta of diabetic animals while nox4 expression remained unchanged
7891NOX4NADPH oxidase 4nox41.9et al showed that in endothelial cells the expression of nox4 markedly exceeded that of gp91 phox and they suggest that
7891NOX4NADPH oxidase 4nox41.9markedly exceeded that of gp91 phox and they suggest that nox4 may function as the major catalytic component of the endothelial
7889NOX1NADPH oxidase 1nox13.2Differential regulation of nox1 and nox4 was also shown in an angiotensin II-induced model
7891NOX4NADPH oxidase 4NOX41.9Differential regulation of nox1 and nox4 was also shown in an angiotensin II-induced model
7891NOX4NADPH oxidase 4nox41.9Differential regulation of nox1 and nox4 was also shown in an angiotensin II-induced model of hypertension
7889NOX1NADPH oxidase 1Nox13.2Nox1 is thought to mediate the agonist-induced superoxide production as its
7891NOX4NADPH oxidase 4nox41.9response to angiotensin II platelet-derived growth factor and serum while nox4 was rather downregulated by these stimuli 35
2707ACEangiotensin I converting enzyme (peptidyl-dipeptidase A) 1ACE0.3Of note ACE activity was found to be increased in the aorta of
2707ACEangiotensin I converting enzyme (peptidyl-dipeptidase A) 1ACE0.3be increased in the aorta of STZ-treated rats 40 while ACE inhibitors as well as angiotensin II blockers were shown to
2707ACEangiotensin I converting enzyme (peptidyl-dipeptidase A) 1ACE0.3In this study we too found an increase in ACE activity in serum of diabetic animals suggesting that activation of
7889NOX1NADPH oxidase 1nox13.2the RAS could lead at least in part to increased nox1 expression and NADPH oxidase activity
7889NOX1NADPH oxidase 1nox13.2may be involved in the agonist-induced superoxide production associated with nox1 in diabetes
7891NOX4NADPH oxidase 4nox41.9is associated with the plasma membrane recent studies have associated nox4 with focal adhesion complexes 43
7889NOX1NADPH oxidase 1nox13.2substantial increase in the expression of the gp91 phox homologue nox1 associated with an increased NADPH oxidase activity in diabetic rat
2578CYBBcytochrome b-245, beta polypeptide (chronic granulomatous disease)nox22.8indicating that this subunit may besides xanthine oxidase mitochondria and nox2 play a role in the vascular dysfunction seen in the
7889NOX1NADPH oxidase 1nox13.2of streptozotocin treatment (_amp_#x201c;Diabetes_amp_#x201d;) _amp_#x201c Diabetes_amp_#x201d on the expression of nox1 and nox4 in rat aorta
7891NOX4NADPH oxidase 4NOX41.9of streptozotocin treatment (_amp_#x201c;Diabetes_amp_#x201d;) _amp_#x201c Diabetes_amp_#x201d on the expression of nox1 and nox4 in rat aorta
7891NOX4NADPH oxidase 4nox41.9treatment (_amp_#x201c;Diabetes_amp_#x201d;) _amp_#x201c Diabetes_amp_#x201d on the expression of nox1 and nox4 in rat aorta
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0the nox2 dependent nadph oxidase was shown to be a major superoxide source in vascular disease including diabetes.
2578CYBBcytochrome b-245, beta polypeptide (chronic granulomatous disease)gp91 phox1.0smooth muscle cells of large arteries lack the phagocytic gp91 phox subunit of the enzyme; however two homologues have been identified in these cells nox1 and nox4.
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0it remained to be established whether also increases in protein levels of the nonphagocytic nadph oxidase contribute to increased superoxide formation in diabetic vessels.
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0this was associated with a significant increase in the nadph oxidase activity in membrane fractions of diabetic heart and aortic tissue.
12805XDHxanthine dehydrogenasexanthine oxidase1.0in addition xanthine oxidase activity was markedly increased in plasma and 100 000 g supernatant of cardiac tissue of diabetic rats while myocardial mitochondrial superoxide formation was only weakly enhanced.
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0we conclude that in addition to phagocytic nadph oxidase also nonphagocytic vascular nadph oxidase subunit nox1 uncoupled nosiii and plasma xanthine oxidase contribute to endothelial dysfunction in the setting of diabetes mellitus.
12805XDHxanthine dehydrogenasexanthine oxidase1.0we conclude that in addition to phagocytic nadph oxidase also nonphagocytic vascular nadph oxidase subunit nox1 uncoupled nosiii and plasma xanthine oxidase contribute to endothelial dysfunction in the setting of diabetes mellitus.
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0subsequent studies with vascular tissue from diabetic animals [1] and patients [2] pointed toward nadph oxidase and an uncoupled nitric oxide synthase nos [3] as potential superoxide sources.
7873NOS2Anitric oxide synthase 2A (inducible, hepatocytes)nitric oxide synthase1.0subsequent studies with vascular tissue from diabetic animals [1] and patients [2] pointed toward nadph oxidase and an uncoupled nitric oxide synthase nos [3] as potential superoxide sources.
12805XDHxanthine dehydrogenasexanthine oxidase1.0furthermore in nonvascular tissues mitochondria [4] and [5] and in plasma xanthine oxidase [6] and [7] were identified as sources of increased superoxide formation in the diabetic state.
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0the vascular nadph oxidase shares several characteristics with the multicomponent enzyme complex described in neutrophils for review see [8] .
2577CYBAcytochrome b-245, alpha polypeptidep22 phox1.0the endothelial the adventitial and the neutrophil nadph oxidase consist of the flavocytochrome b 558 subunits gp91 phox and p22 phox as well as the cytosolic factors p47 phox and p67 phox and the small molecular weight g protein rac 1 [8] .
7661NCF2neutrophil cytosolic factor 2 (65kDa, chronic granulomatous disease, autosomal 2)p67 phox1.0the endothelial the adventitial and the neutrophil nadph oxidase consist of the flavocytochrome b 558 subunits gp91 phox and p22 phox as well as the cytosolic factors p47 phox and p67 phox and the small molecular weight g protein rac 1 [8] .
2578CYBBcytochrome b-245, beta polypeptide (chronic granulomatous disease)gp91 phox1.0the endothelial the adventitial and the neutrophil nadph oxidase consist of the flavocytochrome b 558 subunits gp91 phox and p22 phox as well as the cytosolic factors p47 phox and p67 phox and the small molecular weight g protein rac 1 [8] .
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0the endothelial the adventitial and the neutrophil nadph oxidase consist of the flavocytochrome b 558 subunits gp91 phox and p22 phox as well as the cytosolic factors p47 phox and p67 phox and the small molecular weight g protein rac 1 [8] .
2578CYBBcytochrome b-245, beta polypeptide (chronic granulomatous disease)gp91 phox1.0however smooth muscle cells from large arteries lack gp91 phox but instead express the recently identified gp91 phox homologues nox1 and nox4 [12] and [13] .
6081INSinsulininsulin1.0overexpression of nox1 in fibroblasts and nox4 expression in the kidney increased superoxide production [12] and [15] while nox4 overexpression in adipose cells increased insulin induced hydrogen peroxide production [16] indicating that these nadph oxidase subunits are functionally important.
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0ox4 expression in the kidney increased superoxide production [12] and [15] while nox4 overexpression in adipose cells increased insulin induced hydrogen peroxide production [16] indicating that these nadph oxidase subunits are functionally important.
2577CYBAcytochrome b-245, alpha polypeptidep22 phox1.0recent studies have provided evidence for increased mrna and/or protein levels of gp91 phox p22 phox p47 phox and p67 phox in blood vessels from diabetic animals [1] and diabetic patients [2] .
7661NCF2neutrophil cytosolic factor 2 (65kDa, chronic granulomatous disease, autosomal 2)p67 phox1.0recent studies have provided evidence for increased mrna and/or protein levels of gp91 phox p22 phox p47 phox and p67 phox in blood vessels from diabetic animals [1] and diabetic patients [2] .
2578CYBBcytochrome b-245, beta polypeptide (chronic granulomatous disease)gp91 phox1.0recent studies have provided evidence for increased mrna and/or protein levels of gp91 phox p22 phox p47 phox and p67 phox in blood vessels from diabetic animals [1] and diabetic patients [2] .
2578CYBBcytochrome b-245, beta polypeptide (chronic granulomatous disease)gp91 phox1.0gp91 phox nox1 and nox4 harbor the electron transfer moieties of the enzyme complex and thus serve as the catalytic component; hence regulation of these subunits is considered to be of utmost importance to the
2578CYBBcytochrome b-245, beta polypeptide (chronic granulomatous disease)gp91 phox1.0based on previous studies from our group [1] and others [17] on the role of nox2 gp91 phox in diabetes the effect of streptozotocin induced type i diabetes on the expression of the nadph oxidase subunits nox1 and nox4 and on the vascular nadph oxidase activity was analyzed.
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0based on previous studies from our group [1] and others [17] on the role of nox2 gp91 phox in diabetes the effect of streptozotocin induced type i diabetes on the expression of the nadph oxidase subunits nox1 and nox4 and on the vascular nadph oxidase activity was analyzed.
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0 subunits nox1 and nox4 and on the vascular nadph oxidase activity was analyzed.
12805XDHxanthine dehydrogenasexanthine oxidase1.0measurement of mitochondrial ros formation and xanthine oxidase activity in plasma as well as in soluble fractions of heart homogenates
19986CYCScytochrome c, somaticcytochrome c1.0plasma was obtained from heparin blood and diluted 1:20 in pbs with or without the xanthine oxidase xo substrate hypoxanthine and cytochrome c 50 _amp_#x3bc;m reduction was followed at 550 nm over 10 min.
12805XDHxanthine dehydrogenasexanthine oxidase1.0plasma was obtained from heparin blood and diluted 1:20 in pbs with or without the xanthine oxidase xo substrate hypoxanthine and cytochrome c 50 _amp_#x3bc;m reduction was followed at 550 nm over 10 min.
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))superoxide dismutase1.0xb0;c for 10 min in buffer containing 15 mm tris hcl ph 7.4 3 mm mgcl 2 1.5 mg/ml creatine phosphate 0.1 mg/ml creatine phophokinase 0.9 mg/ml glutathione 0.5 mm isobutylmethylxanthine 1 _amp_#x3bc;m superoxide dismutase 0.5 mm dtpa 0.03 mm l nna 0.1 mm gtp 0.1 mm cgmp.
9958RENreninrenin1.0because of the observed positive effects of ace inhibitors and angiotensin ii receptor blockade the renin/angiotensin system is thought to play a role in cardiovascular complications associated with diabetes [22] .
336AGTR1angiotensin II receptor, type 1angiotensin ii receptor1.0because of the observed positive effects of ace inhibitors and angiotensin ii receptor blockade the renin/angiotensin system is thought to play a role in cardiovascular complications associated with diabetes [22] .
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0to substantiate our more qualitative fluorescent results on vascular superoxide production with a more specific method we assessed the nadph oxidase activity in membrane fractions of both heart and aortic tissue from control and diabetic rats by lucigenin 5 _amp_#x3bc;m derived cl either with or without the addition of 200 _amp_#x3bc;m nadph.
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0the nadph oxidase activity in membrane fractions from the heart was about 5 fold higher than the activity in the aortic membranes fig 3 .
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0the addition of dpi 10 _amp_#x3bc;m a nonspecific flavoprotein and nadph oxidase inhibitor normalized the nadph induced cl signal in the heart membranes to near background levels.
12805XDHxanthine dehydrogenasexanthine oxidase1.0to exclude the presence of mitochondria as well as xanthine oxidase in the used cardiac membrane fractions nadh 200 _amp_#x3bc;m rotenone 10 _amp_#x3bc;m an inhibitor of mitochondrial respiration and hypoxanthine 1 mm a substrate of xanthine oxidase were added but fa
12805XDHxanthine dehydrogenasexanthine oxidase1.0 in the used cardiac membrane fractions nadh 200 _amp_#x3bc;m rotenone 10 _amp_#x3bc;m an inhibitor of mitochondrial respiration and hypoxanthine 1 mm a substrate of xanthine oxidase were added but failed to show any significant effect on the basal cl signal results not shown .
12805XDHxanthine dehydrogenasexanthine oxidase1.0effect of stz treatment on the mitochondrial ros formation and xanthine oxidase activity in plasma as well as in soluble fractions of heart homogenates
19986CYCScytochrome c, somaticcytochrome c1.0since xanthine oxidase reportedly increases in diabetes we also assessed superoxide formation by this enzyme in plasma and 100 000 g supernatant of heart homogenates using cytochrome c as a superoxide detector.
12805XDHxanthine dehydrogenasexanthine oxidase1.0since xanthine oxidase reportedly increases in diabetes we also assessed superoxide formation by this enzyme in plasma and 100 000 g supernatant of heart homogenates using cytochrome c as a superoxide detector.
12805XDHxanthine dehydrogenasexanthine oxidase1.0xanthine oxidase dependent superoxide formation was increased by 5 fold in the supernatant of heart homogenates and by approximately 80% in plasma although this latter increase was not significant p _amp_#xa0;=_amp_#
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0in order to identify the nadph oxidase isoform s that may play a role in the increased superoxide formation in diabetic aortas we analyzed protein extracts from diabetic and control aortas by western blotting using specific antibodies for
2578CYBBcytochrome b-245, beta polypeptide (chronic granulomatous disease)gp91 phox1.0in the present study we provide the first evidence for upregulation of the gp91 phox homologue nox1 in the aorta from type i diabetic animals.
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0increased expression of nox1 was associated with an increase in nadph oxidase activity in aortic membrane fractions and similarly increased nadph oxidase activity was also detected in heart membranes of diabetic rats.
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0besides nadph oxidase mitochondria and xanthine oxidase contributed to increased superoxide formation in the cardiac tissue.
12805XDHxanthine dehydrogenasexanthine oxidase1.0besides nadph oxidase mitochondria and xanthine oxidase contributed to increased superoxide formation in the cardiac tissue.
12805XDHxanthine dehydrogenasexanthine oxidase1.0as shown previously also nox2 [1] and [17] mitochondria [4] and [5] and xanthine oxidase [6] and [7] will contribute to oxidative stress in diabetes.
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0le cells exposed to high concentrations of glucose as well as in vessels from diabetic animals and patients was inhibited by dpi pointing to the involvement of a flavin containing oxidase such as the nadph oxidase as a significant superoxide source [2] [28] and [29] .
12805XDHxanthine dehydrogenasexanthine oxidase1.0however since dpi also inhibits xanthine oxidase no synthase and mitochondrial flavoenzymes these may potentially contribute to superoxide formation.
12805XDHxanthine dehydrogenasexanthine oxidase1.0as another superoxide source xanthine oxidase contributes to oxidative stress in type 1 and 2 diabetes [6] [7] and [31] .
12805XDHxanthine dehydrogenasexanthine oxidase1.0consistent with these earlier reports we observed a marked increase in xanthine oxidase hypoxanthine dependent superoxide formation in 100 000 g supernatant from heart homogenates from diabetic rats possibly representing plasma xanthine oxidase adhering to the luminal endothelial side o
12805XDHxanthine dehydrogenasexanthine oxidase1.0 hypoxanthine dependent superoxide formation in 100 000 g supernatant from heart homogenates from diabetic rats possibly representing plasma xanthine oxidase adhering to the luminal endothelial side of myocardial vessels.
12805XDHxanthine dehydrogenasexanthine oxidase1.0it has been shown that increased plasma xanthine oxidase in stz diabetic rats affected endothelial function by adhering to the luminal surface of endothelial cells [7] .
12805XDHxanthine dehydrogenasexanthine oxidase1.0we may therefore not exclude the possibility that slightly increased plasma xanthine oxidase activity contributed to endothelial dysfunction observed in the present study.
12805XDHxanthine dehydrogenasexanthine oxidase1.0however plasma xanthine oxidase cannot account for diabetes induced superoxide formation observed in other parts of the vascular wall e.g. the media and adventitia.
2577CYBAcytochrome b-245, alpha polypeptidep22 phox1.0recent studies with vascular tissue from diabetic animals and patients revealed increased nadph oxidase activity as well as increased expression of the nadph oxidase subunits p22 phox and gp91 phox as well as p47 phox and p67 phox at the mrna and protein level respectively [1] [2] and [32] .
7661NCF2neutrophil cytosolic factor 2 (65kDa, chronic granulomatous disease, autosomal 2)p67 phox1.0scular tissue from diabetic animals and patients revealed increased nadph oxidase activity as well as increased expression of the nadph oxidase subunits p22 phox and gp91 phox as well as p47 phox and p67 phox at the mrna and protein level respectively [1] [2] and [32] .
2578CYBBcytochrome b-245, beta polypeptide (chronic granulomatous disease)gp91 phox1.0recent studies with vascular tissue from diabetic animals and patients revealed increased nadph oxidase activity as well as increased expression of the nadph oxidase subunits p22 phox and gp91 phox as well as p47 phox and p67 phox at the mrna and protein level respectively [1] [2] and [32] .
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0recent studies with vascular tissue from diabetic animals and patients revealed increased nadph oxidase activity as well as increased expression of the nadph oxidase subunits p22 phox and gp91 phox as well as p47 phox and p67 phox at the mrna and protein level respectively [1] [2] and [32] .
2578CYBBcytochrome b-245, beta polypeptide (chronic granulomatous disease)gp91 phox1.0however these observations most likely do not reflect reactive oxygen species produced in the arterial media since gp91 phox is not the catalytic subunit in smooth muscle cells from large arteries.
2577CYBAcytochrome b-245, alpha polypeptidep22 phox1.0interestingly in vessels from atherosclerotic monkeys increased levels of the nadph oxidase subunits p22 phox and p47 phox colocalized with macrophages [32] .
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0interestingly in vessels from atherosclerotic monkeys increased levels of the nadph oxidase subunits p22 phox and p47 phox colocalized with macrophages [32] .
2578CYBBcytochrome b-245, beta polypeptide (chronic granulomatous disease)gp91 phox1.0smooth muscle cells of large arteries lack gp91 phox but instead express the homologues nox1 and nox4.
333AGTangiotensinogen (serpin peptidase inhibitor, clade A, member 8)angiotensin ii1.0angiotensin ii infusion [34] as well as carotid injury [33] drastically increases nox1 expression with no or minor change in nox4 expression.
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0a critical question is whether increased expression of the nadph oxidase subunit is translated into increased nadph oxidase activity.
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0however when using nadh to drive the nadph oxidase and high lucigenin concentrations as the detector a considerable degree of redox cycling occurs which raises doubts of whether increased nadh mediated superoxide production reflects increases in the
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0nin concentrations as the detector a considerable degree of redox cycling occurs which raises doubts of whether increased nadh mediated superoxide production reflects increases in the activity of the nadph oxidase or whether this is artificial [37] .
12805XDHxanthine dehydrogenasexanthine oxidase1.0neither rotenone inhibitor of mitochondrial superoxide production nor hypoxanthine xanthine oxidase substrate affected basal superoxide formation as expected for a pure membrane preparation.
2578CYBBcytochrome b-245, beta polypeptide (chronic granulomatous disease)gp91 phox1.0in the same study we showed an upregulation of gp91 phox mrna the nadph oxidase subunit found in endothelial cells the adventitia and inflammatory cells.
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0in the same study we showed an upregulation of gp91 phox mrna the nadph oxidase subunit found in endothelial cells the adventitia and inflammatory cells.
2578CYBBcytochrome b-245, beta polypeptide (chronic granulomatous disease)gp91 phox1.0we postulated that a large part of the increase in gp91 phox is likely to be secondary to infiltration of inflammatory cells.
2578CYBBcytochrome b-245, beta polypeptide (chronic granulomatous disease)gp91 phox1.0in fact a recent study by ago et al. showed that in endothelial cells the expression of nox4 markedly exceeded that of gp91 phox and they suggest that nox4 may function as the major catalytic component of the endothelial nadph oxidase [39] .
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0y by ago et al. showed that in endothelial cells the expression of nox4 markedly exceeded that of gp91 phox and they suggest that nox4 may function as the major catalytic component of the endothelial nadph oxidase [39] .
333AGTangiotensinogen (serpin peptidase inhibitor, clade A, member 8)angiotensin ii1.0differential regulation of nox1 and nox4 was also shown in an angiotensin ii induced model of hypertension [34] and in a model of restenosis after balloon injury [33] .
8800PDGFBplatelet-derived growth factor beta polypeptide (simian sarcoma viral (v-sis) oncogene homolog)platelet derived growth factor1.0nox1 is thought to mediate the agonist induced superoxide production as its mrna in smooth muscle cells was markedly upregulated in response to angiotensin ii platelet derived growth factor and serum while nox4 was rather downregulated by these stimuli [35] .
333AGTangiotensinogen (serpin peptidase inhibitor, clade A, member 8)angiotensin ii1.0nox1 is thought to mediate the agonist induced superoxide production as its mrna in smooth muscle cells was markedly upregulated in response to angiotensin ii platelet derived growth factor and serum while nox4 was rather downregulated by these stimuli [35] .
333AGTangiotensinogen (serpin peptidase inhibitor, clade A, member 8)angiotensin ii1.0of note ace activity was found to be increased in the aorta of stz treated rats [40] while ace inhibitors as well as angiotensin ii blockers were shown to improve vascular complications associated with diabetes [22] .
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0in this study we too found an increase in ace activity in serum of diabetic animals suggesting that activation of the ras could lead at least in part to increased nox1 expression and nadph oxidase activity.
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0interestingly a recent study showed that age were able to activate a nadph oxidase in human endothelial cells which was inhibitable by dpi [42] .
2578CYBBcytochrome b-245, beta polypeptide (chronic granulomatous disease)gp91 phox1.0while gp91 phox is associated with the plasma membrane recent studies have associated nox4 with focal adhesion complexes [43] .
2578CYBBcytochrome b-245, beta polypeptide (chronic granulomatous disease)gp91 phox1.0taken together the present study demonstrates for the first time a substantial increase in the expression of the gp91 phox homologue nox1 associated with an increased nadph oxidase activity in diabetic rat aorta indicating that this subunit may besides xanthine oxidase mitochondria and nox2 play a role in the vascular dy
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0taken together the present study demonstrates for the first time a substantial increase in the expression of the gp91 phox homologue nox1 associated with an increased nadph oxidase activity in diabetic rat aorta indicating that this subunit may besides xanthine oxidase mitochondria and nox2 play a role in the vascular dysfunction seen in the setting of diabetes mellitus.
12805XDHxanthine dehydrogenasexanthine oxidase1.0 first time a substantial increase in the expression of the gp91 phox homologue nox1 associated with an increased nadph oxidase activity in diabetic rat aorta indicating that this subunit may besides xanthine oxidase mitochondria and nox2 play a role in the vascular dysfunction seen in the setting of diabetes mellitus.
14874NOX5NADPH oxidase, EF-hand calcium binding domain 5nadph oxidase1.0fig. 3._amp_#xa0;effect of the streptozotocin treatment _amp_#x201c;diabetes_amp_#x201d; on the nadph oxidase activity in aorta and heart of rats.
7889NOX1NADPH oxidase 1nadph oxidase 11.0ator agents|vasodilator stimulated phosphoprotein|nitric oxide|superoxides|acetylcholine|nitroglycerin|nitric oxide synthase|xanthine oxidase|nadh nadph oxidoreductases|nox4 protein rat|nadph oxidase|nadph oxidase 1|