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)

Arsenic in drinking water is a major public health concern as it increases risk and incidence of cardiovascular disease and cancer. Arsenic exposure affects multiple vascular beds, promoting liver sinusoidal capillarization and portal hypertension, ischemic heart disease, peripheral vascular disease, and tumor angiogenesis. While Rac1-GTPase and NADPH oxidase activities are essential for arsenic-stimulated endothelial cell signaling for angiogenesis or liver sinusoid capillarization, the mechanism for initiating these effects is unknown. We found that arsenic-stimulated cell signaling and angiogenic gene expression in human microvascular endothelial cells were Pertussis toxin sensitive, indicating a G-protein coupled signaling pathway. Incubating human microvascular endothelial cells with the sphingosine-1-phosphate type 1 receptor (S1P(1)) inhibitor VPC23019 or performing small interfering RNA knockdown of S1P(1) blocked arsenic-stimulated HMVEC angiogenic gene expression and tube formation, but did not affect induction of either HMOX1 or IL8. Liver sinusoidal endothelial cells (LSECs) defenestrate and capillarize in response to aging and environmental oxidant stresses. We found that S1P(1) was enriched on LSECs in vivo and in primary cell culture and that VPC23019 inhibited both sphingosine-1-phosphate-stimulated and arsenic-stimulated LSEC oxidant generation and defenestration. These studies identified novel roles for S1P(1) in mediating arsenic stimulation of both angiogenesis and pathogenic LSEC capillarization, as well as demonstrating a role for S1P(1) in mediating environmental responses in the liver vasculature, providing possible mechanistic insight into arsenic-induced vascular pathogenesis and disease.
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PMID:Arsenic requires sphingosine-1-phosphate type 1 receptors to induce angiogenic genes and endothelial cell remodeling. 1934 68

The development of immunosuppressant compounds, such as cyclosporine and tacrolimus was crucial to the success of transplant surgery and for treatment of autoimmune diseases. However, immunosuppressant therapy may increase the concentrations of reactive oxygen species (ROS), inducing oxidative damage such as an increased vascular damage. The major source of ROS in the vascular endothelial cells is NADPH oxidase. The subunit structure and function of this enzyme complex in vascular cells differs from that in phagocytic leucocytes. The enzyme subunits Nox1, Nox2 and Nox4 are only found in vascular cells. The GTP-dependent protein subunit Rac 1 needs to be activated for this enzyme to function. Inhibiting this protein subunit should reduce NADPH oxidase-induced oxidative stress. In the cardiovascular system, oxidative stress is observed as hypertension, hypertrophy, fibrosis, conduction abnormalities and endothelial dysfunction, as well as cardiac allograft vasculopathy in transplant patients. In contrast to cyclosporine and tacrolimus, the immunosuppressant mycophenolate inhibits the Rac 1 subunit thus inhibiting NADPH oxidase in the vasculature. This may reduce oxidative stress, prevent the development of cardiac allograft vasculopathy, decrease the deterioration of vascular function and improve cardiovascular function chronically in transplant patients. This overview discusses whether this antioxidant immunosuppressive property could translate into a more general protective role for mycophenolate in the prevention of cardiovascular disease.
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PMID:Is mycophenolate more than just an immunosuppressant?--An overview. 1937 50

1. Additive beneficial effects on cardiovascular disease have been reported for amlodipine and atorvastatin. However, it is still unclear whether the combination of amlodipine and atorvastatin has additive beneficial effects on the regression of advanced cardiac hypertrophy in hypertension. In the present study, the effects of the drug combination on advanced cardiac hypertrophy were investigated in elderly spontaneously hypertensive rats (SHR). 2. Elderly SHR (36 weeks old) were randomly allocated into four groups of 12: (i) a vehicle-treated control group; (ii) an amlodipine (10 mg/kg per day)-treated group; (iii) an atorvastatin (10 mg/kg per day)-treated group; and (iv) a group treated with a combination of amlodipine and atorvastatin (both at 10 mg/kg per day). Drugs were administered by oral gavage every morning for a period of 12 weeks before hearts were harvested for analysis. 3. Combined administration of amlodipine and atorvastatin significantly suppressed cardiomyocyte hypertrophy, interstitial fibrosis and upregulation of hypertrophic and profibrotic genes, and also improved left ventricular diastolic dysfunction to a greater extent than did amlodipine monotherapy. Further beneficial effects of combination therapy on advanced cardiac hypertrophy were associated with a greater reduction of NADPH oxidase-mediated increases in cardiac reactive oxygen species (ROS), rather than decreased blood pressure and serum cholesterol levels. 4. To elucidate the underlying molecular mechanisms, we examined cardiovascular NADPH oxidase subunits and found that amlodipine clearly attenuated the expression of p47(phox) and p40(phox) and slightly but significantly reduced p22(phox) and Rac-1 levels in heart tissue. Combination treatment with amlodipine plus atorvastatin led to a further reduction in p22(phox), p47(phox) and Rac-1 protein levels compared with amlodipine alone. 5. In conclusion, combined amlodipine and atorvastatin treatment has a greater beneficial effect on advanced cardiac hypertrophy compared with amlodipine monotherapy. The benefits are likely to be related to the additive effects of the drugs on the suppression of NADPH oxidase-mediated ROS generation.
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PMID:Additive beneficial effects of amlodipine and atorvastatin in reversing advanced cardiac hypertrophy in elderly spontaneously hypertensive rats. 1941 92

The relationship between HTNand other components of the CMSis complex. However, there is growing evidence that enhanced activation of the RAAS is a key factor in the development of endothelial dysfunction and HTN. Insulin resistance is induced by activation of the RAAS and resulting increases in ROS. This insulin resistance occurs in cardiovascular tissue and in tissues traditionally considered as targets for the action of insulin, such as muscle and liver. Indeed, there is a mounting body of evidence that the resultant insulin resistance in cardiovascular tissue and kidneys contributes to the development of endothelial dysfunction, HTN, atherosclerosis, CKD, and CVD.77 RAAS-associated signaling by way of the AT1R and MR, triggers tissue activation of the NADPH oxidase enzymatic activation and increased production of ROS. Oxidative stress in cardiovascular tissue is derived from both NADPH oxidase and mitochondrial generation of ROS, and is central to the development of insulin resistance, endothelial dysfunction, HTN, and atherosclerosis. Pharmacologic blockade of the RAAS not only improves blood pressure, but alsohas a beneficial impact on inflammation, oxidative stress, insulin sensitivity, and glucose homeostasis. Several strategies are available for RAAS blockade, including ACE inhibitors, ARBs, and MR blockers, which have been proven in the clinical trials to result in improved CVD and CKD outcomes. New research in these areas will allow for a better understanding of the relationship between HTN, insulin resistance, and activation of the RAAS, which could result in newer alternatives for a more comprehensive management of HTN in the setting of the CMS..
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PMID:The renin angiotensin aldosterone system in hypertension: roles of insulin resistance and oxidative stress. 1942 92

This review has summarized some of the data supporting a role of ROS and oxidant stress in the genesis of hypertension. There is evidence that hypertensive stimuli, such as high salt and angiotensin II, promote the production of ROS in the brain, the kidney, and the vasculature and that each of these sites contributes either to hypertension or to the untoward sequelae of this disease. Although the NADPH oxidase in these various organs is a predominant source, other enzymes likely contribute to ROS production and signaling in these tissues. A major clinical challenge is that the routinely used antioxidants are ineffective in preventing or treating cardiovascular disease and hypertension. This is likely because these drugs are either ineffective or act in a non-targeted fashion, such that they remove not only injurious ROS Fig. 5. Proposed role of T cells in the genesis of hypertension and the role of the NADPH oxidase in multiple cells/organs in modulating this effect. In this scenario, angiotensin II stimulates an NADPH oxidase in the CVOs of the brain, increasing sympathetic outflow. Sympathetic nerve terminals in lymph nodes activate T cells, and angiotensin II also directly activates T cells. These stimuli also activate expression of homing signals in the vessel and likely the kidney, which attract T cells to these organs. T cells release cytokines that stimulate the vessel and kidney NADPH oxidases, promoting vasoconstriction and sodium retention. SFO, subfornical organ. 630 Harrison & Gongora but also those involved in normal cell signaling. A potentially important and relatively new direction is the concept that inflammatory cells such as T cells contribute to hypertension. Future studies are needed to understand the interaction of T cells with the CNS, the kidney, and the vasculature and how this might be interrupted to provide therapeutic benefit.
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PMID:Oxidative stress and hypertension. 1942 95

Increased oxidative stress is a known cause of cardiac dysfunction in animals and patients with diabetes, but the sources of reactive oxygen species [e.g., superoxide anion (O(2)(-))] and the mechanisms underlying O(2)(-) production in diabetic hearts are not clearly understood. Our aim was to determine whether NADPH oxidase (Nox) is a source of O(2)(-) and whether glucose-6-phosphate dehydrogenase (G6PD)-derived NADPH plays a role in augmenting O(2)(-) generation in diabetes. We assessed cardiac function, Nox and G6PD activities, NADPH levels, and the activities of antioxidant enzymes in heart homogenates from young (9-11 wk old) Zucker lean and obese (fa/fa) rats. We found that myocardial G6PD activity was significantly higher in fa/fa than in lean rats, whereas superoxide dismutase and glutathione peroxidase activities were decreased (P < 0.05). O(2)(-) levels were elevated (70-90%; P < 0.05) in the diabetic heart, and this elevation was blocked by the Nox inhibitor gp-91(ds-tat) (50 microM) or by the mitochondrial respiratory chain inhibitors antimycin (10 microM) and rotenone (50 microM). Inhibition of G6PD by 6-aminonicotinamide (5 mM) and dihydroepiandrosterone (100 microM) also reduced (P < 0.05) O(2)(-) production. Notably, the activities of Nox and G6PD in the fa/fa rat heart were inhibited by chelerythrine, a protein kinase C inhibitor. Although we detected no changes in stroke volume, cardiac output, or ejection fraction, left ventricular diameter was slightly increased during diastole and systole, and left ventricular posterior wall thickness was decreased during systole (P < 0.05) in Zucker fa/fa rats. Our findings suggest that in a model of severe hyperlipidema and hyperglycemia Nox-derived O(2)(-) generation in the myocardium is fueled by elevated levels of G6PD-derived NADPH. Similar mechanisms were found to activate O(2)(-) production and induce endothelial dysfunction in aorta. Thus G6PD may be a useful therapeutic target for treating the cardiovascular disease associated with type 2 diabetes, if second-generation drugs specifically reducing the activity of G6PD to near normal levels are developed.
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PMID:Superoxide production by NAD(P)H oxidase and mitochondria is increased in genetically obese and hyperglycemic rat heart and aorta before the development of cardiac dysfunction. The role of glucose-6-phosphate dehydrogenase-derived NADPH. 1942 15

The rostral ventrolateral medulla (RVLM), a region critical for the tonic and reflex control of arterial pressure, contains a group of adrenergic (C1) neurons that project to the spinal cord and directly modulate pre-ganglionic sympathetic neurons. Epidemiological data suggest that there are gender differences in the regulation of blood pressure. One factor that could be involved is angiotensin II signaling and the associated production of reactive oxygen species (ROS) by NADPH oxidase, which is emerging as an important molecular substrate for central autonomic regulation and dysregulation. In this study dual electron microscopic immunolabeling was used to examine the subcellular distribution of the angiotensin type 1 (AT(1)) receptor and two NADPH oxidase subunits (p47 and p22) in C1 dendritic processes, in tissue from male, proestrus (high estrogen) and diestrus (low estrogen) female rats. Female dendrites displayed significantly more AT(1) labeling and significantly less p47 labeling than males. While elevations in AT(1) labeling primarily resulted from higher levels of receptor on the plasma membrane, p47 labeling was reduced both on the plasma membrane and in the cytoplasm. Across the estrous cycle, proestrus females displayed significantly higher levels of AT(1) labeling than diestrus females, which resulted exclusively from plasma membrane density differences. In contrast, p47 labeling did not change across the estrous cycle, indicating that ROS production might reflect AT(1) receptor membrane density. No significant differences in p22 labeling were observed. These findings demonstrate that both sex and hormonal levels can selectively affect the expression and subcellular distribution of components of the angiotensin II signaling pathway within C1 RVLM neurons. Such effects could reflect differences in the capacity for ROS production, potentially influencing short term excitability and long term gene expression in a cell group which is critically involved in blood pressure regulation, potentially contributing to gender differences in the risk of cardiovascular disease.
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PMID:Sex differences in the subcellular distribution of angiotensin type 1 receptors and NADPH oxidase subunits in the dendrites of C1 neurons in the rat rostral ventrolateral medulla. 1950 31

Arginase has been reported to reduce nitric oxide bioavailability in cardiovascular disease. However, its specific role in retinopathy has not been studied. In this study, we assessed the role of arginase in a mouse model of endotoxin-induced uveitis induced by lipopolysaccharide (LPS) treatment. Measurement of arginase expression and activity in the retina revealed a significant increase in arginase activity that was associated with increases in both mRNA and protein levels of arginase (Arg)1 but not Arg2. Immunofluorescence and flow cytometry confirmed this increase in Arg1, which was localized to glia and microglia. Arg1 expression and activity were also increased in cultured Muller cells and microglia treated with LPS. To test whether arginase has a role in the development of retinal inflammation, experiments were performed in mice deficient in one copy of the Arg1 gene and both copies of the Arg2 gene or in mice treated with a selective arginase inhibitor. These studies showed that LPS-induced increases in inflammatory protein production, leukostasis, retinal damage, signs of anterior uveitis, and uncoupling of nitric oxide synthase were blocked by either knockdown or inhibition of arginase. Furthermore, the LPS-induced increase in Arg1 expression was abrogated by blocking NADPH oxidase. In conclusion, these studies suggest that LPS-induced retinal inflammation in endotoxin-induced uveitis is mediated by NADPH oxidase-dependent increases in arginase activity.
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PMID:Arginase activity mediates retinal inflammation in endotoxin-induced uveitis. 1959 38

Appreciation for the role of aldosterone and mineralocorticoid receptors in cardiovascular disease is accelerating rapidly. Recent experimental work has unveiled a strong relationship between brain mineralocorticoid receptors and sympathetic drive, an important determinant of outcome in heart failure and hypertension. Two putative mechanisms are explored in this manuscript. First, brain mineralocorticoid receptors may influence sympathetic discharge by regulating the release of pro-inflammatory cytokines into the circulation. Blood-borne pro-inflammatory cytokines act upon receptors in the microvasculature of the brain to induce cyclooxygenase-2 activity and the production of prostaglandin E(2), which penetrates the blood-brain barrier to activate the sympathetic nervous system. Second, brain mineralocorticoid receptors may influence sympathetic drive by upregulating the activity of the brain renin-angiotensin system, resulting in NAD(P)H oxidase-dependent superoxide production. A potential role for superoxide-dependent mitogen-activated protein kinase signalling pathways in the regulation of sympathetic nerve activity is also considered. Other potential downstream signalling mechanisms contributing to mineralocorticoid receptor-mediated sympathetic excitation are under investigation.
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PMID:Mineralocorticoid receptors, inflammation and sympathetic drive in a rat model of systolic heart failure. 2006 26

Single nucleotide polymorphisms (SNP) in the CYBA gene encoding p22(phox) have been associated with respiratory burst and cardiovascular phenotypes. We previously reported a reduced phagocytic respiratory burst activity in healthy adults with the C242T SNP, but found no correlation between CYBA SNPs and coronary artery disease (CAD) phenotype. Using lymphoblastoid cells, we hypothesized that CYBA SNPs affect enzyme activity in patients with cardiovascular disease (CVD), but would not be associated with angiographic severity of CAD due to confounding by risk factors. We established lymphoblastoid cell lines from patients with CVD and genotyped the study cohort for CYBA SNPs and phenotyped each subject's coronary angiogram for CAD severity. As quantified by electron spin resonance, superoxide production in picomoles per 10(6) resting lymphoblastoid cells per minute for the CC, CT, and TT genotypes of the C242T SNP were 16.2+/-1.4, n=70, 11.9+/-0.7, n=87, and 11.9+/-1.5, n=28, respectively (P=0.002). The -930(A/G) and A640G SNPs did not affect superoxide production (P > 0.2). Expression of p22(phox) was not affected as determined by real-time RT-PCR and Western blot analysis. The C242T CYBA SNP is associated with altered NADPH oxidase activity in lymphoblastoid cells of patients with CVD. By reducing the influence of confounding environmental factors, lymphoblastoid cell lines could serve as a tool to assess direct genotype/phenotype interactions of candidate genes known to affect atherosclerosis.
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PMID:The C242T CYBA polymorphism as a major determinant of NADPH oxidase activity in patients with cardiovascular disease. 1968 63


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