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)

It has been suggested the the interaction of Escherichia coli O157-derived verotoxins (VTs) with the vascular endothelium plays a central role in the pathogenesis of the thrombotic microangiopathy and ischemic lesions characteristic of hemolytic uremic syndrome (HUS) and E. coli O157-associated hemorrhagic colitis. Intravenous administration of both E. coli O157-derived VT1 and lipopolysaccharide (LPS) in the rat induced a synergistic increase in thiobarbituric acid (TBA) values in those animal's plasma, as compared with that injected with VT1 or LPS alone. We then hypothesized that an increase in lipid peroxidation in the rat plasma was due to an enhanced production of endothelial cell-derived reactive oxidant. Based on determination of rat sera and cultured human aortic endothelial cells (HAECs), VT1 had little if any effect on LPS-stimulated increase of nitric oxide and the resultant peroxynitrite generations. Both RT-PCR and Western blot studies of reactive oxygen species-related enzymes showed that VT1 markedly decreased the expression of catalase mRNA and protein in HAECs, but caused less alteration in the levels of Cu, Zn-superoxide dismutase, and NADPH oxidase mRNA. Further studies by spin trapping analysis using 5, 5-dimethyl-1-pyrroline-N-oxide (DMPO) revealed a time-dependent increase in hydroxyl radicals by VT1 in HAECs. The accumulated data thus suggest that bacterial VT1 reduces mainly catalase levels in endothelial cells, which is synergistically potentiated by LPS, and that the resulting hydroxyl radical participates in endothelium injury through a marked enhancement of lipid peroxidation, leading to HUS.
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PMID:Reactive oxygen species as a risk factor in verotoxin-1-exposed rats. 1040 47

The mechanisms that lead to organ injury in hypertension are incompletely understood. In particular, there is a lack of evidence that serves to link the elevation of arterial blood pressure with end organ damage. Experimental models of hypertension have a range of microvascular abnormalities in addition to a shift in blood pressure. There is evidence for an oxidative stress in microvascular endothelium derived from xanthine and NADPH oxidase. Furthermore, there exists an immune suppression accompanied by abnormally elevated circulating leukocyte counts, depression of selectin membrane adhesion to the endothelium and enhanced cell apoptosis. Many of the deficiencies in the spontaneously hypertensive rats can be corrected by adrenalectomy, suggesting a contribution of glucocorticoids to the abnormalities in this model. These observations suggest a significantly enhanced vascular oxidative stress which is accompanied by a frustrated inflammatory response due to a glucocorticoid dependent deficiency of leukocyte adhesion to vascular endothelium.
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PMID:Microvascular oxidative stress, immune reaction and apoptosis in hypertensives. 1071 38

The vascular endothelium synthesizes and releases a spectrum of vasoactive substances like nitric oxide (NO) and endothelin (ET). In hypertension, the delicate balance of endothelium-derived factors is disturbed. ET acts as the natural counterpart to endothelium-derived NO, which exerts vasodilating, antithrombotic, and antiproliferative effects, and inhibits leukocyte-adhesion to the vascular wall. Besides its blood pressure rising effect also in man, ET induces vascular and myocardial hypertrophy, which are independent risk factors for cardiovascular morbidity and mortality. The derangement of endothelial function in hypertension is likely to be caused in part by genetic factors, but also due to elevated blood pressure itself. Due to its position between blood pressure and smooth muscle cells responsible for peripheral resistance, the endothelium is thought to be both target and mediator of arterial hypertension. Oxidative stress plays an important role in the pathogenesis of hypertension. Superoxide anions, ie, oxygen radicals produced in part by angiotensin II-activated NAD(P)H oxidase, can scavenge NO to form peroxynitrite, which can nitrosylate membrane proteins and oxidize lipids. Another source of superoxide is cyclooxygenase. Paradoxically, dysfunctional endothelial NO synthase may also be a source of superoxide anions. Surprisingly and in contrast to animal experiments, not all antihypertensive treatments consistently restore endothelium-dependent vasodilation in patients with arterial hypertension. Endothelial dysfunction in hypertension is crucial both for the development of the disease process in the vasculature and an important therapeutic target.
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PMID:Working under pressure: the vascular endothelium in arterial hypertension. 1109 55

Coronary microvascular endothelial cells exert (patho)physiological effects on the function of cardiac myocytes, which may be studied experimentally using pure cell populations. As an essential pre-requisite to the investigation of cells from gene-modified mice, we studied the phenotypic properties of coronary microvascular endothelial cells isolated from normal mice, and biochemically characterized the superoxide production by these cells. Microvascular endothelial cells were isolated from devitalized mouse ventricular tissue after sequential digestion with collagenase, trypsin and DNase. Coronary microvascular endothelial cells were separated from cardiac myocytes and other cells by differential centrifugation, plating and culture. Mouse coronary microvascular endothelial cells showed an irregular "cobblestone" morphology at confluence, were >98% positive for CD31 by FACS analysis, and were also positive for VE-cadherin and endothelial-type nitric oxide synthase (eNOS) by confocal microscopy. The cells took up fluorescently labelled, acetylated low-density lipoprotein, but were negative for a alpha -smooth muscle actin, desmin and cytokeratin. Unlike human endothelial cells, mouse coronary microvascular endothelial cells only weakly expressed von Willebrand factor. Immunoblotting showed that the mouse cells expressed components of a phagocyte-type NADPH oxidase. They exhibited NADPH-dependent O(2)(-)-generating activity, which was increased by angiotensin II but completely inhibited by diphenyleneiodonium. Thus, mouse coronary microvascular endothelial cells express both eNOS and NADPH oxidase, interactions between which may play a role in endothelial cell pathophysiology.
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PMID:Phenotypic properties and characteristics of superoxide production by mouse coronary microvascular endothelial cells. 1144 17

Hyperoxia increases reactive oxygen species (ROS) production in vascular endothelium; however, the mechanisms involved in ROS generation are not well characterized. We determined the role and regulation of NAD(P)H oxidase in hyperoxia-induced ROS formation in human pulmonary artery endothelial cells (HPAECs). Exposure of HPAECs to hyperoxia for 1, 3, and 12 h increased the generation of superoxide anion, which was blocked by diphenyleneiodonium but not by rotenone or oxypurinol. Furthermore, hyperoxia enhanced NADPH- and NADH-dependent and superoxide dismutase- or diphenyleneiodonium-inhibitable ROS production in HPAECs. Immunohistocytochemistry and Western blotting revealed the presence of gp91, p67 phox, p22 phox, and p47 phox subcomponents of NADPH oxidase in HPAECs. Transfection of HPAECs with p22 phox antisense plasmid inhibited hyperoxia-induced ROS production. Exposure of HPAECs to hyperoxia activated p38 MAPK and ERK, and inhibition of p38 MAPK and MEK1/2 attenuated the hyperoxia-induced ROS generation. These results suggest a role for MAPK in regulating hyperoxia-induced NAD(P)H oxidase activation in HPAECs.
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PMID:Hyperoxia-induced NAD(P)H oxidase activation and regulation by MAP kinases in human lung endothelial cells. 1247 Oct 12

The vascular adventitia is activated in a variety of cardiovascular disease states and has recently been shown to be a barrier to nitric oxide bioactivity. Vascular fibroblasts produce substantial amounts of NAD(P)H oxidase-derived reactive oxygen species (ROS) that appear to be involved in fibroblast proliferation, connective tissue deposition, and perhaps vascular tone. However, the physiological and pathophysiological roles of the adventitia have not been extensively studied, possibly because of its location in large blood vessels remote from the vascular endothelium. In recent years, substantial information has been gathered on pathways leading to oxidase activation in smooth muscle cells and fibroblasts and the downstream signaling pathways leading to hypertrophy and proliferation. A clearer understanding of the molecular mechanisms involved will likely lead to therapeutic strategies aimed at preventing vascular dysfunction in diseases such as atherosclerosis, in which these pathways are activated.
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PMID:The reactive adventitia: fibroblast oxidase in vascular function. 1248 20

Common vascular disease states including diabetes, hypertension and atherosclerosis are associated with endothelial dysfunction, characterised by reduced bioactivity of nitric oxide (NO). Loss of the vasculoprotective effects of NO contributes to disease progression, but the mechanisms underlying endothelial dysfunction remain unclear. Increased superoxide production in animal models of vascular disease contributes to reduced NO bioavailability, endothelial dysfunction and oxidative stress. In human blood vessels, the NAD(P)H oxidase system is the principal source of superoxide, and is functionally related to clinical risk factors and systemic endothelial dysfunction. Furthermore, the C242T polymorphism in the NAD(P)H oxidase p22phox subunit is associated with significantly reduced superoxide production in patients carrying the 242T allele, suggesting a role for genetic variation in modulating vascular superoxide production. In vessels from patients with diabetes mellitus, endothelial dysfunction, NAD(P)H oxidase activity and protein subunits are significantly increased compared with matched non-diabetic vessels. Furthermore, the vascular endothelium in diabetic vessels is a net source of superoxide rather than NO production, due to dysfunction of endothelial NO synthase (eNOS). This deficit is dependent on the eNOS cofactor, tetrahydrobiopterin, and is in part mediated by protein kinase C signalling. These studies suggest an important role for both the NAD(P)H oxidases and endothelial NOS in the increased vascular superoxide production and endothelial dysfunction in human vascular disease states.
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PMID:Mechanisms of superoxide production in human blood vessels: relationship to endothelial dysfunction, clinical and genetic risk factors. 1251 89

Glucocorticoid (GC) excess often elicits serious adverse effects on the vascular system, such as hypertension and atherosclerosis, and effective prophylaxis for these complications is limited. We sought to reveal the mechanism underlying GC-induced vascular complications. Responses in forearm blood flow to reactive hyperemia in 20 GC-treated patients were significantly decreased to 43+/-8.9% (mean+/-SEM) from the values obtained before GC therapy (130+/-14%). An administration of vitamin C almost normalized blood flow responses. In human umbilical vein endothelial cells (HUVECs), production of hydrogen peroxide was increased up to 166.5+/-3.3% of control values by 10(-7) mol/L dexamethasone (DEX) treatment (P<0.01). Concomitant with DEX-induced hydrogen peroxide production, intracellular amounts of peroxynitrite significantly increased and those of nitric oxide (NO) decreased, respectively (P<0.01). Immunoblotting analysis using anti-nitrotyrosine antibody showed that peroxynitrite formation was increased in DEX-treated HUVECs. Using inhibitors against metabolic pathways for generation of reactive oxygen species (ROS), we identified that the major production sources of ROS by DEX treatment were mitochondrial electron transport chain, NAD(P)H oxidase, and xanthine oxidase. These findings suggest that GC excess causes overproduction of ROS and thereby perturbs NO availability in the vascular endothelium, leading to vascular complications in patients with GC excess.
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PMID:Glucocorticoid excess induces superoxide production in vascular endothelial cells and elicits vascular endothelial dysfunction. 1252 24

Oxidative stress occurs when the production of reactive oxygen species (ROS) exceeds the capacity of the cell to detoxify these potentially injurious oxidants using endogenous antioxidant defense systems. Conditions associated with oxidative stress include ischemia/reperfusion, hypercholesterolemia, diabetes, and hypertension. The adhesion of circulating blood cells (leukocytes, platelets) to vascular endothelium is a key element of the pro-inflammatory and prothrombogenic phenotype assumed by the vasculature in these and other disease states that are associated with an oxidative stress. There is a growing body of evidence that links the blood cell endothelial cell interactions in these conditions to the enhanced production of ROS. Potential enzymatic sources of ROS within the microcirculation include xanthine oxidase, NAD(P)H oxidase, and nitric oxide synthase. ROS can promote a pro-inflammatory/prothrombogenic phenotype within the microvasculature by a variety of mechanisms, including the inactivation of nitric oxide, the activation of redox-sensitive transcription factors (e.g., nuclear factor-kappaB) that govern the expression of endothelial cell adhesion molecules (e.g., P-selectin), and the activation of enzymes (e.g., phospholipase A(2)) that produce leukocyte-stimulating inflammatory mediators (e.g., platelet-activating factor). The extensively documented ability of different oxidant-ablating interventions to attenuate blood cell endothelial cell interactions underscores the importance of ROS in mediating the dysfunctional microvascular responses to oxidative stress.
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PMID:Oxidative stress promotes blood cell-endothelial cell interactions in the microcirculation. 1266 63

Individuals who eat salty diets and who are "salt-sensitive" tend to have increased left ventricular mass, independent of blood pressure; this phenomenon awaits an explanation. It is clear that local up-regulation of angiotensin II (AngII) production and activity play a key role in the induction of left ventricular hypertrophy (LVH). Recent evidence suggests that a healthy coronary microvascular endothelium opposes this effect by serving as a paracrine source of nitric oxide (NO), a natural antagonist of AngII activity, and that up-regulation of this mechanism can account for the protective role of bradykinin with respect to LVH. The coronary microvasculature also possesses NAD(P)H oxidase activity that can generate superoxide, inimical to the bioactivity of endothelial NO. There is now good reason to believe that the triterpenoid marinobufagenin (MBG), a selective inhibitor of the alpha-1 isoform of the sodium pump, mediates the impact of salty diets on blood pressure;production of MBG by the adrenal cortex is boosted when salt-sensitive animals are fed salty diets. It is hypothesized that coronary microvascular endothelium expresses the alpha-1 isoform of the sodium pump, and that MBG thus can target this endothelium. If that is the case, MBG would be expected to decrease membrane potential in these cells;as a consequence, superoxide production would be up-regulated, NO synthase activity would be down-regulated, and myocardial NO bioactivity would thus be suppressed. This would offer a satisfying explanation for the impact of salt and salt-sensitivity on risk for LVH. If expression of the alpha-1 isoform of the sodium pump is a more general property of vascular endothelium, MBG may suppress NO bioactivity in other regions of the vascular tree, thereby contributing to other adverse effects elicited by salty diets: reduced arterial compliance, medial hypertrophy, impaired endothelium-dependent vasodilation, hypertensive/diabetic glomerulopathy, increased risk for stroke, and hypertension.
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PMID:Marinobufagenin may mediate the impact of salty diets on left ventricular hypertrophy by disrupting the protective function of coronary microvascular endothelium. 1514 63


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