Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.6.3.1 (NADPH oxidase)
11,281 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The renin-angiotensin-aldosterone system contributes to cardiac remodeling, hypertrophy, and left ventricular dysfunction. Angiotensin II and aldosterone (corticosterone in rodents) together generate reactive oxygen species (ROS) via reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, which likely facilitate this hypertrophy and remodeling. This investigation sought to determine whether cardiac oxidative stress and cellular remodeling could be attenuated by in vivo mineralocorticoid receptor (MR) blockade in a rodent model of the chronically elevated tissue renin-angiotensin-aldosterone system, the transgenic TG (mRen2) 27 rat (Ren2). The Ren2 overexpresses the mouse renin transgene with resultant hypertension, insulin resistance, proteinuria, and cardiovascular damage. Young (6- to 7-wk-old) male Ren2 and age-matched Sprague-Dawley rats were treated with spironolactone or placebo for 3 wk. Heart tissue ROS, immunohistochemical analysis of 3-nitrotyrosine, and NADPH oxidase (NOX) subunits (gp91(phox) recently renamed NOX2, p22(phox), Rac1, NOX1, and NOX4) were measured. Structural changes were assessed with cine-magnetic resonance imaging, transmission electron microscopy, and light microscopy. Significant increases in Ren2 septal wall thickness (cine-magnetic resonance imaging) were accompanied by perivascular fibrosis, increased mitochondria, and other ultrastructural changes visible by light microscopy and transmission electron microscopy. Although there was no significant reduction in systolic blood pressure, significant improvements were seen with MR blockade on ROS formation and NOX subunits (each P < 0.05). Collectively, these data suggest that MR blockade, independent of systolic blood pressure reduction, improves cardiac oxidative stress-induced structural and functional changes, which are driven, in part, by angiotensin type 1 receptor-mediated increases in NOX.
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PMID:Mineralocorticoid receptor blockade attenuates chronic overexpression of the renin-angiotensin-aldosterone system stimulation of reduced nicotinamide adenine dinucleotide phosphate oxidase and cardiac remodeling. 1749 96

We recently identified a local pancreatic islet renin-angiotensin system (RAS), and demonstrated that it is upregulated in an animal model of obesity-induced type 2 diabetes mellitus (T2DM). Moreover, angiotensin II type 1 receptor (AT1R) antagonism improves beta-cell function and glucose tolerance in young T2DM mice and delays the onset of diabetes. Meanwhile, obesity-induced T2DM results in oxidative stress-mediated activation of uncoupling protein 2 (UCP2), a negative regulator of islet function. In the present study, we postulated that some of the protective effects of AT1R antagonism might be mediated through interference with this pathway and tested this hypothesis in a T2DM animal model. Losartan, an AT1R antagonist, was given to 4-week-old obese db/db mice for a period of 8 weeks. UCP2-driven oxidative damage and apoptosis were then analyzed in isolated islets. Losartan selectively inhibited oxidative stress via downregulation of NADPH oxidase; this in turn suppressed UCP2 expression, thus improving beta-cell insulin secretion and decreasing apoptosis-induced beta-cell mass loss in db/db mouse islets. These data indicate that islet AT1R activation in young diabetic mice can generate progressive islet beta-cell failure through UCP-driven oxidative damage.
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PMID:Angiotensin II Type 1 receptor antagonism mediates uncoupling protein 2-driven oxidative stress and ameliorates pancreatic islet beta-cell function in young Type 2 diabetic mice. 1750 12

The incidence of obesity, cardiometabolic syndrome (CMS), and type 2 diabetes mellitus (DM2), as well as their devastating cardiovascular consequences, keep rising with increasing human and economical costs. For a long time, insulin resistance has been the main player in the pathogenesis and treatment of DM2, but every day more knowledge is gained about the central role of beta-cell failure, not only in the appearance of hyperglycemia but also in the failure of the pharmacological therapy. beta-Cell failure implies impairment of glucosestimulated insulin secretion and loss of beta-cell mass. Hyperglycemia, elevated circulating fatty acids, inadequate local activation of renin angiotensin system, and chronic low grade inflammation are conditions that coexist in the CMS and DM2 that turn out to be deleterious for the beta-cell functioning and existance. Excessive oxidative stress secondary to increased production of reactive oxygen species and decreased availability of antioxidants is a possible common converging point of the multiple noxious stimuli. Activation of the NADPH oxidase complex secondary to angiotensin II stimulation is of interest, as its pharmacological blockade has beneficial effects. New knowledge about the intimate mechanisms of oxidative-stress induced beta-cell failure will provide new therapeutic targets against CMS and DM2.
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PMID:The expanding role of oxidative stress, renin angiotensin system, and beta-cell dysfunction in the cardiometabolic syndrome and Type 2 diabetes mellitus. 1750 16

Reduced insulin sensitivity is characteristic of various pathological conditions such as type 2 diabetes mellitus and hypertension. Angiotensin II, acting through its angiotensin type 1 receptor, inhibits the actions of insulin in the vasculature which may lead to deleterious effects such as vascular inflammation, remodeling, endothelial dysfunction, and insulin resistance. In contrast, insulin normally exerts vasodilatory, antiinflammatory, and prosurvival actions. To explore the impact of angiotensin II on insulin signaling, NADPH oxidase-derived reactive oxygen species formation, vascular inflammation, apoptosis, and remodeling, we used transgenic TG(mRen2)27 (Ren2) rats, which harbor the mouse renin transgene and exhibits elevated tissue angiotensin II levels. Compared with Sprague-Dawley controls, Ren2 aortas exhibited greater NADPH oxidase activity, reactive oxygen species levels, C-reactive protein, tumor necrosis factor-alpha expression, apoptosis, and wall thickness, which were significantly attenuated by in vivo treatment with angiotensin type 1 receptor blockade (valsartan) or the superoxide dismutase/catalase mimetic (tempol). There was substantially diminished Akt and endothelial NO synthase activation in Ren2 aortas in response to in vivo insulin stimulation, and this was significantly improved by in vivo treatment with valsartan or tempol. In vivo treatment with valsartan, but not tempol, significantly reduced blood pressure in Ren2 rats. Further, there was reduced insulin induced Akt activation and increased tumor necrosis factor-alpha levels in vascular smooth muscle cells from Ren2 and Sprague-Dawley rats treated with angiotensin II, abnormalities that were abrogated by angiotensin type 1 receptor blockade with valsartan or antioxidant N-acetylcysteine. Collectively, these data suggest that increased angiotensin type 1 receptor/NADPH oxidase activation/reactive oxygen species contribute to vascular insulin resistance, endothelial dysfunction, apoptosis, and inflammation.
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PMID:NADPH oxidase contributes to vascular inflammation, insulin resistance, and remodeling in the transgenic (mRen2) rat. 1753 99

Insulin resistance combined with hyperinsulinemia is involved in the generation of oxidative stress. There is known to be a relationship between increased production of reactive oxygen species and the diverse pathogenic mechanisms involved in diabetic vascular complications including nephropathy. The present study found that high doses of insulin affect mesangial cell proliferation through the generation of intracellular reactive oxygen species and the activation of cell signaling pathways. We also examined whether azelnidipine, a dihydropyridine-based calcium antagonist with established antioxidant activity, has the potential to inhibit mesangial cell proliferation. Cell proliferation was increased in a dose-dependent manner by high doses of insulin (0.1-10 microM), but was inhibited by 0.1 microM azelnidipine. Phosphorylation of extracellular signal-regulated kinase (ERK)-1/2 was found to be increased by insulin in a dose-dependent manner (0.1-10 microM). This increased phosphorylation of ERK-1/2 was inhibited by treatment with 0.1 microM azelnidipine. Intracellular oxidative stress was also increased by insulin stimulation in a dose-dependent manner (0.01-10 microM), and 0.1 microM azelnidipine was found to block intracellular reactive oxygen species production more effectively than 0.1 microM nifedipine. The NAD(P)H oxidase inhibitor, apocynin (0.01-0.1 microM), prevented insulin-induced mesangial cell proliferation. Taken together, these results suggest that azelnidipine inhibits insulin-induced mesangial cell proliferation by inhibiting the production of reactive oxygen species. Given these pharmacological characteristics, azelnidipine may have the potential to protect against the onset of diabetic nephropathy and slow its progression.
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PMID:Antioxidative effects of azelnidipine on mesangial cell proliferation induced by highly concentrated insulin. 1754 93

Insulin, in the permissive presence of nitric oxide (NO), stimulates cGMP production which inhibits autonomous calcium/calmodulin-dependent protein kinase II (CaM kinase II) thereby inhibiting cultured vascular smooth muscle cell (VSMC) migration. In the presence of angiotensin II (Ang II), insulin stimulates NAD(P)H oxidase activity leading to increased VSMC migration. We wished to see whether insulin-stimulated cGMP stimulates protein phosphatase-2A (PP-2A) thereby inhibiting autonomous CaM kinase II and migration, and whether insulin, in the presence of Ang II, inhibits PP-2A and stimulates autonomous CaM kinase II in a NAD(P)H oxidase-dependent manner. One nanomole per litre of insulin in the presence of NO, or 50 micromol/L 8-Br-cGMP stimulated PP-2A activity by 46+/-6 and 247+/-23%, respectively (both P<0.05), and 8-Br-cGMP inhibited autonomous CaM kinase II activity by 67+/-9% (P<0.05) by a 10 nmol/L okadaic acid-sensitive pathway. Insulin plus Ang II inhibited PP-2A activity by 57+/-7% (P<0.05) and stimulated autonomous CaM kinase II activity by 120+/-14% (P<0.05), both by an apocynin-sensitive pathway. 8-Br-cGMP-inhibited VSMC migration was blocked by okadaic acid. It is concluded that insulin in the presence of NO stimulates cGMP which stimulates PP-2A activity causing inhibition of autonomous CaM kinase II activity and thus VSMC migration, and that insulin in the presence of Ang II inhibits PP-2A and stimulates autonomous CaM kinase II activities by a NAD(P)H oxidase-dependent mechanism which are associated with insulin-stimulated NAD(P)H oxidase-dependent migration.
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PMID:Insulin-inhibited and stimulated cultured vascular smooth muscle cell migration are related to divergent effects on protein phosphatase-2A and autonomous calcium/calmodulin-dependent protein kinase II. 1755 5

Adipocyte differentiation is a complex process regulated among other factors by insulin and the production of reactive oxygen species (ROS). NOX4 is a ROS generating NADPH oxidase enzyme mediating insulin's action in 3T3L1 adipocytes. In the present paper we show that NOX4 is expressed at high levels both in white and brown preadipocytes and that differentiation into adipocytes results in a decrease in their NOX4 mRNA content. These in vitro results were confirmed in vivo by demonstrating that in intact adipose tissue the majority of NOX4 expressing cells are localized within the preadipocyte containing stromal/vascular fraction, rather than in the portion consisting of mature adipocytes. In line with these observations, quantification of NOX4 mRNA in fat derived from different rodent models of insulin resistance indicated that alteration in NOX4 expression reflects changes in the ratio of adipocyte/interstitial fractions. In conclusion, we reveal that decreased NOX4 mRNA content is a hallmark of adipocyte differentiation and that NOX4 expression measured in whole adipose tissue is not an unequivocal indicator of intact or impaired insulin action.
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PMID:Reduced expression of the NADPH oxidase NOX4 is a hallmark of adipocyte differentiation. 1755 79

The reduced capacity of insulin to stimulate glucose transport into skeletal muscle, termed insulin resistance, is a primary defect leading to the development of prediabetes and overt type 2 diabetes. Although the etiology of this skeletal muscle insulin resistance is multifactorial, there is accumulating evidence that one contributor is overactivity of the renin-angiotensin system (RAS). Angiotensin II (ANG II) produced from this system can act on ANG II type 1 receptors both in the vascular endothelium and in myocytes, with an enhancement of the intracellular production of reactive oxygen species (ROS). Evidence from animal model and cultured skeletal muscle cell line studies indicates ANG II can induce insulin resistance. Chronic ANG II infusion into an insulin-sensitive rat produces a markedly insulin-resistant state that is associated with a negative impact of ROS on the skeletal muscle glucose transport system. ANG II treatment of L6 myocytes causes impaired insulin receptor substrate (IRS)-1-dependent insulin signaling that is accompanied by augmentation of NADPH oxidase-mediated ROS production. Further critical evidence has been obtained from the TG(mREN2)27 rat, a model of RAS overactivity and insulin resistance. The TG(mREN2)27 rat displays whole body and skeletal muscle insulin resistance that is associated with local oxidative stress and a significant reduction in the functionality of the insulin receptor (IR)/IRS-1-dependent insulin signaling. Treatment with a selective ANG II type 1 receptor antagonist leads to improvements in whole body insulin sensitivity, enhanced insulin-stimulated glucose transport in muscle, and reduced local oxidative stress. In addition, exercise training of TG(mREN2)27 rats enhances whole body and skeletal muscle insulin action. However, these metabolic improvements elicited by antagonism of ANG II action or exercise training are independent of upregulation of IR/IRS-1-dependent signaling. Collectively, these findings support targeting the RAS in the design of interventions to improve metabolic and cardiovascular function in conditions of insulin resistance associated with prediabetes and type 2 diabetes.
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PMID:Improvement of insulin sensitivity by antagonism of the renin-angiotensin system. 1758 38

It is now widely accepted, given the current weight of experimental evidence, that reactive oxygen species (ROS) contribute to cell and tissue dysfunction and damage caused by glucolipotoxicity in diabetes. The source of ROS in the insulin secreting pancreatic beta-cells and in the cells which are targets for insulin action has been considered to be the mitochondrial electron transport chain. While this source is undoubtably important, we provide additional information and evidence for NADPH oxidase-dependent generation of ROS both in pancreatic beta-cells and in insulin sensitive cells. While mitochondrial ROS generation may be important for regulation of mitochondrial uncoupling protein (UCP) activity and thus disruption of cellular energy metabolism, the NADPH oxidase associated ROS may alter parameters of signal transduction, insulin secretion, insulin action and cell proliferation or cell death. Thus NADPH oxidase may be a useful target for intervention strategies based on reversing the negative impact of glucolipotoxicity in diabetes.
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PMID:Diabetes associated cell stress and dysfunction: role of mitochondrial and non-mitochondrial ROS production and activity. 1758 43

Chronic fish oil intervention had been shown to have a positive impact on endothelial function. Although high-fat meals have often been associated with a loss of postprandial vascular reactivity, studies examining the effects of fish oil fatty acids on vascular function in the postprandial phase are limited. The aim of the present study was to examine the impact of the addition of fish oil fatty acids to a standard test meal on postprandial vascular reactivity. A total of 25 men received in a random order either a placebo oil meal (40 g of mixed fat; fatty acid profile representative of the U.K. diet) or a fish oil meal (31 g of mixed fat and 9 g of fish oil) on two occasions. Vascular reactivity was measured at baseline (0 h) and 4 h after the meal by laser Doppler iontophoresis, and blood samples were taken for the measurement of plasma lipids, total nitrite, glucose and insulin. eNOS (endothelial NO synthase) and NADPH oxidase gene expression were determined in endothelial cells after incubation with TRLs (triacylglycerol-rich lipoproteins) isolated from the plasma samples taken at 4 h. Compared with baseline, sodium nitroprusside (an endothelium-independent vasodilator)-induced reactivity (P=0.024) and plasma nitrite levels (P=0.001) were increased after the fish oil meal. In endothelial cells, postprandial TRLs isolated after the fish oil meal increased eNOS and decreased NADPH oxidase gene expression compared with TRLs isolated following the placebo oil meal (P</=0.03). In conclusion, meal fatty acids appear to be an important determinant of vascular reactivity, with fish oils significantly improving postprandial endothelium-independent vasodilation.
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PMID:Fish oil fatty acids improve postprandial vascular reactivity in healthy men. 1805 25


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