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:1.6.99.6 (NADPH oxidase)
10,295 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Abrupt reduction of flow (ischemia) leads to endothelial cell membrane depolarization, NADPH oxidase activation, and reactive oxygen species (ROS) generation in isolated rat and mouse lungs and in flow-adapted endothelial cells in vitro. Here we evaluated the role of PI-3-kinase and rac in activation of endothelial NADPH oxidase. Endothelium of isolated perfused mouse lungs labeled with 2',7'-dichlorodihydrofluorescein (H(2)DCF) or hydroethidine (HE) showed increased ROS generation with ischemia; these results were supported by TBARS measurement in whole-lung homogenate and by in vitro studies using flow-adapted mouse pulmonary microvascular endothelial cells. Ischemia-induced ROS generation in intact lung or isolated cells was blocked by pretreatment with Clostridium difficile toxin B, a rac inhibitor, and by wortmannin or LY294002, PI3 kinase inhibitors. In cells, immunofluorescence and immunoblot after subcellular fractionation showed ischemia-induced translocation of rac, p47(phox), and p67(phox) to the plasma membrane. Increased extracellular K(+) also resulted in rac translocation, providing evidence that this pathway is sensitive to alterations of endothelial cell membrane potential. These results indicate that PI-3-kinase and the small G protein rac are involved in the activation of endothelial cell NADPH oxidase that is associated with the acute loss of shear stress.
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PMID:Rac and PI3 kinase mediate endothelial cell-reactive oxygen species generation during normoxic lung ischemia. 1816 54

Aerobic metabolism generates biologically challenging reactive oxygen species (ROS) by the endogenous autooxidation of components of the electron transport chain (ETC). Basal levels of oxidative stress can dramatically rise upon activation of the NADPH oxidase-dependent respiratory burst. To minimize ROS toxicity, prokaryotic and eukaryotic organisms express a battery of low-molecular-weight thiol scavengers, a legion of detoxifying catalases, peroxidases, and superoxide dismutases, as well as a variety of repair systems. We present herein blockage of bacterial respiration as a novel strategy that helps the intracellular pathogen Salmonella survive extreme oxidative stress conditions. A Salmonella strain bearing mutations in complex I NADH dehydrogenases is refractory to the early NADPH oxidase-dependent antimicrobial activity of IFNgamma-activated macrophages. The ability of NADH-rich, complex I-deficient Salmonella to survive oxidative stress is associated with resistance to peroxynitrite (ONOO(-)) and hydrogen peroxide (H(2)O(2)). Inhibition of respiration with nitric oxide (NO) also triggered a protective adaptive response against oxidative stress. Expression of the NDH-II dehydrogenase decreases NADH levels, thereby abrogating resistance of NO-adapted Salmonella to H(2)O(2). NADH antagonizes the hydroxyl radical (OH(.)) generated in classical Fenton chemistry or spontaneous decomposition of peroxynitrous acid (ONOOH), while fueling AhpCF alkylhydroperoxidase. Together, these findings identify the accumulation of NADH following the NO-mediated inhibition of Salmonella's ETC as a novel antioxidant strategy. NO-dependent respiratory arrest may help mitochondria and a plethora of organisms cope with oxidative stress engendered in situations as diverse as aerobic respiration, ischemia reperfusion, and inflammation.
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PMID:Nitric oxide evokes an adaptive response to oxidative stress by arresting respiration. 1819 79

The generation of reactive oxygen species (ROS) represents a pivotal element of phagocyte defense against microbial invaders. However, oxidative stress also participates in pathophysiological processes of vascular damage leading to cell death of endothelial cells (EC). Currently, ROS-producing cells involved in this process as well as the corresponding extracellular signals required for their activation are ill-defined. In this study, we investigate the impact of the platelet-derived CXC chemokine platelet factor 4 (PF4/CXCL4) on the interaction of human monocytes and EC. We can show for the first time that PF4-activated monocytes become cytotoxic for EC but not epithelial cells. Cytotoxicity was time- and dose-dependent, and earliest effects were seen after 15 h of culture and at a concentration from 0.125 microM PF4 up. By performing transwell experiments and by using specific inhibitory antibodies, we could show that direct cell contact between effector and target cells, mediated by beta(2)integrins as well as their corresponding ligand ICAM-1, is essential for the cytotoxic effect. Investigations of the cellular mechanisms of cytotoxicity revealed that in the presence of EC, PF4-activated monocytes are capable of releasing high amounts of ROS for more than 2 h following stimulation. This causes programmed cell death in EC, as inhibitors of the NADPH oxidase (diphenyleneiodonium and apocynin) effectively blocked PF4-induced monocyte oxidative burst and protected EC from undergoing apoptosis. Taken together, our data suggest a role for platelet-derived PF4 in oxidative stress-mediated vascular disorders, as observed during atherosclerosis or ischemia/reperfusion injury.
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PMID:Platelet factor 4/CXCL4-stimulated human monocytes induce apoptosis in endothelial cells by the release of oxygen radicals. 1820 73

Endothelial dysfunction comprising impairment of endothelium-dependent vasodilator function and increased endothelial activation contributes to the pathophysiology of cardiovascular diseases such as atherosclerosis, diabetic vasculopathy, heart failure and hypertension. The changes in endothelial phenotype in these conditions occur in response to diverse stimuli including inflammatory cytokines, activation of renin-angiotensin-aldosterone system, hyperlipidaemia, hyperglycemia, ischemia-reperfusion and mechanical forces. An increased production of reactive oxygen species (ROS), such as superoxide and H(2)O(2) is involved in the genesis of these alterations in endothelial phenotype. The NADPH oxidases, Nox2 and Nox4, are major sources of ROS in endothelial cells and are implicated both in vasodilator dysfunction and in the modulation of redox-sensitive signalling pathways that influence endothelial cytoskeletal organisation, adhesion molecule expression, permeability, growth, migration and other functions. NADPH oxidases appear to be especially important in redox signalling in that they are specifically activated by diverse agonists and regulate the activation of downstream protein kinases, transcription factors and other biological molecules. This review provides an overview of NADPH oxidase structure and regulation in endothelial cells and their role in pathophysiology, focussing particularly on endothelial activation.
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PMID:NADPH oxidase-derived reactive oxygen species in the regulation of endothelial phenotype. 1827 82

Angiogenesis is essential for tumor growth, metastasis, arteriosclerosis as well as embryonic development and wound healing. Its process is dependent on cell proliferation, migration and capillary tube formation in endothelia cells (ECs). High levels of reactive oxygen species (ROS) such as superoxide and H2O2 are observed in various cancer cells. Accumulating evidence suggests that ROS function as signaling molecules to mediate various growth-related responses including angiogenesis. ROS-dependent angiogenesis can be regulated by endogenous antioxidant enzymes such as SOD and thioredoxin. Vascular endothelial growth factor (VEGF), one of the major angiogenesis factor, is induced in growing tumors and stimulates EC proliferation and migration primarily through the VEGF receptor type2 (VEGFR2, Flk1/KDR). Major source of ROS in ECs is a NADPH oxidase which consists of Nox1, Nox2, Nox4, Nox5, p22phox, p47phox and the small G-protein Rac1. NADPH oxidase is activated by various growth factors including VEGF and angiopoietin-1 as well as hypoxia and ischemia, and ROS derived from this oxidase are involved in VEGFR2 autophosphorylation, and diverse redox signaling pathways leading to induction of transcription factors and genes involved in angiogenesis. Dietary antioxidants appear to be effective for treatment of tumor angiogenesis. The aim of this review is to provide an overview of the recent progress on role of ROS derived from NADPH oxidase and redox signaling events involved in angiogenesis. Understanding these mechanisms may provide insight into the NADPH oxidase and redox signaling components as potential therapeutic targets for tumor angiogenesis.
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PMID:Reactive oxygen species and angiogenesis: NADPH oxidase as target for cancer therapy. 1840 51

Inflammation following ischemic stroke is known to contribute to injury. NADPH oxidase (NOX) is a major enzyme system originally studied in immune cells that leads to superoxide (O.*) generation. Apocynin is a NOX inhibitor that has been studied as a potential treatment in experimental stroke. Here we explored the effect of different doses of apocynin in a mouse model of 2 h transient middle cerebral artery occlusion (tMCAO) followed by 22 h reperfusion. Apocynin, given i.v. at a dose of 2.5 mg/kg 30 min before reperfusion, improved neurological function (P<0.01), reduced infarct volume (P<0.05), and reduced the incidence of cerebral hemorrhage (P<0.05), but not at higher doses of 3.75 and 5 mg/kg, where it actually increased brain hemorrhage. Apocynin also tended to reduce mortality at the lower dose, but not at higher doses. Using hydroethine fluorescence to delineate O.* in the brain, neurons and some microglia/macrophages, but not vascular endothelial cells were found to contain O.*. Apocynin at protective doses markedly prevented ischemia-induced increases in O.*. Our data suggested that apocynin can protect against experimental stroke, but with a narrow therapeutic window.
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PMID:Apocynin improves outcome in experimental stroke with a narrow dose range. 1851 Dec 5

Abrupt cessation of flow representing the acute loss of shear stress (simulated ischemia) to flow-adapted pulmonary microvascular endothelial cells (PMVEC) leads to reactive oxygen species (ROS) generation that signals for EC proliferation. We evaluated the role of caveolin-1 on this cellular response with mouse PMVEC that were preconditioned for 72 h to laminar flow at 5 dyn/cm(2) followed by stop of flow ("ischemia"). Preconditioning resulted in a 2.7-fold increase in cellular expression of K(ATP) (K(IR) 6.2) channels but no change in expression level of caveolin-1, gp91(phox), or MAP kinases. The initial response to ischemia in wild type cells was cell membrane depolarization that was abolished by gene targeting of K(IR) 6.2. The subsequent response was increased ROS production associated with activation of NADPH oxidase (NOX2) and then phosphorylation of MAP kinases (Erk, JNK). After 24 h of ischemia in wild type cells, the cell proliferation index increased 2.5 fold and the % of cells in S+G(2)/M phases increased 6-fold. This signaling cascade (cell membrane depolarization, ROS production, MAP kinase activation and cell proliferation) was abrogated in caveolin-1 null PMVEC or by treatment of wild type cells with filipin. These studies indicate that caveolin-1 functions as a shear sensor in flow-adapted EC resulting in ROS-mediated cell signaling and endothelial cell proliferation following the abrupt reduction in flow.
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PMID:Caveolae are an essential component of the pathway for endothelial cell signaling associated with abrupt reduction of shear stress. 1857 85

Bone marrow (BM) is the major reservoir for endothelial progenitor cells (EPCs). Postnatal neovascularization depends on not only angiogenesis but also vasculogenesis, which is mediated through mobilization of EPCs from BM and their recruitment to the ischemic sites. Reactive oxygen species (ROS) derived from Nox2-based NADPH oxidase play an important role in postnatal neovascularization; however, their role in BM and EPC function is unknown. Here we show that hindlimb ischemia of mice significantly increases Nox2 expression and ROS production in BM-mononuclear cells (BMCs), which is associated with an increase in circulating EPC-like cells. Mice lacking Nox2 show reduction of ischemia-induced flow recovery, ROS levels in BMCs, as well as EPC mobilization from BM. Transplantation of wild-type (WT)-BM into Nox2-deficient mice rescues the defective neovascularization, whereas WT mice transplanted with Nox2-deficient BM show reduced flow recovery and capillary density compared to WT-BM transplanted control. Intravenous infusion of WT- and Nox2-deficient BMCs into WT mice reveals that neovascularization and homing capacity are impaired in Nox2-deficient BMCs in vivo. In vitro, Nox2-deficient c-kit+Lin- BM stem/progenitor cells show impaired chemotaxis and invasion as well as polarization of actins in response to stromal derived factor (SDF), which is associated with blunted SDF-1-mediated phosphorylation of Akt. In conclusion, Nox2-derived ROS in BM play a critical role in mobilization, homing, and angiogenic capacity of EPCs and BM stem/progenitor cells, thereby promoting revascularization of ischemic tissue. Thus, NADPH oxidase in BM and EPCs is potential therapeutic targets for promoting neovascularization in ischemic cardiovascular diseases.
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PMID:Role of nox2-based NADPH oxidase in bone marrow and progenitor cell function involved in neovascularization induced by hindlimb ischemia. 1858 11

Diminished bioavailability of nitric oxide is a hallmark of endothelial dysfunction and is associated with a broad spectrum of vascular disorders such as impaired angiogenesis. Because Rac1, a Rho family member, mediates cellular motility and generation of reactive oxygen species, it could be involved in the regulation of endothelial nitric oxide production. However, the pathophysiological consequences of postnatal endothelial Rac1 deletion on endothelial function have not been determined. We generated endothelial-specific Rac1 haploinsufficient mice (EC-Rac1(+/-)) using Cre-loxP technology. The EC-Rac1(+/-) mice have decreased expression and activity of endothelial nitric oxide synthase (eNOS), impaired endothelium-dependent vasorelaxation, and mild hypertension compared with control (Rac1(+/flox)) mice. Hind limb ischemia model and aortic capillary sprouting assay showed that eNOS activity and angiogenesis was impaired in EC-Rac1(+/-) mice. Indeed, Rac1 promotes eNOS gene transcription through p21-activated kinase but not NADPH oxidase, increases eNOS mRNA stability, and enhances eNOS activity by promoting endothelial uptake of l-arginine. These findings indicate that endothelial Rac1 is essential for endothelium-dependent vasomotor response and ischemia-induced angiogenesis. These effects of Rac1 on endothelial function are largely due to the upregulation of eNOS through multiple mechanisms that are mediated, in part, by p21-activated kinase. Therapeutic strategies to enhance Rac1 function, therefore, may be important for preventing endothelial dysfunction.
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PMID:Regulation of endothelial nitric oxide synthase and postnatal angiogenesis by Rac1. 1870 82

Decreased cerebral blood flow (CBF) has been observed following the resuscitation from neonatal hypoxic-ischemic injury, but its mechanism is not known. We address the hypothesis that reduced CBF is due to a change in nitric oxide (NO) and superoxide anion O(2)(-) balance secondary to endothelial NO synthase (eNOS) uncoupling with vascular injury. Wistar rats (7 day old) were subjected to cerebral hypoxia-ischemia by unilateral carotid occlusion under isoflurane anesthesia followed by hypoxia with hyperoxic or normoxic resuscitation. Expired CO(2) was determined during the period of hyperoxic or normoxic resuscitation. Laser-Doppler flowmetry was used with isoflurane anesthesia to monitor CBF, and cerebral perivascular NO and O(2)(-) were determined using fluorescent dyes with fluorescence microscopy. The effect of tetrahydrobiopterin supplementation on each of these measurements and the effect of apocynin and N(omega)-nitro-L-arginine methyl ester (L-NAME) administration on NO and O(2)(-) were determined. As a result, CBF in the ischemic cortex declined following the onset of resuscitation with 100% O(2) (hyperoxic resuscitation) but not room air (normoxic resuscitation). Expired CO(2) was decreased at the onset of resuscitation, but recovery was the same in normoxic and hyperoxic resuscitated groups. Perivascular NO-induced fluorescence intensity declined, and O(2)(-)-induced fluorescence increased in the ischemic cortex after hyperoxic resuscitation up to 24 h postischemia. L-NAME treatment reduced O(2)(-) relative to the nonischemic cortex. Apocynin treatment increased NO and reduced O(2)(-) relative to the nonischemic cortex. The administration of tetrahydrobiopterin following the injury increased perivascular NO, reduced perivascular O(2)(-), and increased CBF during hyperoxic resuscitation. These results demonstrate that reduced CBF follows hyperoxic resuscitation but not normoxic resuscitation after neonatal hypoxic-ischemic injury, accompanied by a reduction in perivascular production of NO and an increase in O(2)(-). The finding that tetrahydrobiopterin, apocynin, and L-NAME normalized radical production suggests that the uncoupling of perivascular NOS, probably eNOS, due to acquired relative tetrahydrobiopterin deficiency occurs after neonatal hypoxic-ischemic brain injury. It appears that both NOS uncoupling and the activation of NADPH oxidase participate in the changes of reactive oxygen concentrations seen in cerebral hypoxic-ischemic injury.
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PMID:Perivascular nitric oxide and superoxide in neonatal cerebral hypoxia-ischemia. 1870 40


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