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)

Laminar shear stress activates NADPH oxidase in vascular endothelial cells (ECs), and the generated superoxide radicals (O2(-.) are known to be involved in intercellular adhesion molecule (ICAM)-1 expression. In this study, the role of a glycosphingolipid (GSL), lactosylceramide (LacCer), as a second messenger in the shear-induced O2(-.) generation and ICAM-1 expression was examined. It is known that glucosylceramide synthase (GlcT-1) catalyzes the synthesis of glucosylceramide (GlcCer) from ceramide, and subsequently lactosylceramide synthase (GalT-2) synthesizes LacCer from GlcCer. We observed that exposing cultured human umbilical vein ECs (HUVECs) to fluid shear stress (20 dyn/cm(2) for 30 min) activated GalT-2. Shear stress also increased EC O2(-.) generation, that peaked at 30 min, and surface ICAM-1 protein expression at 6 h post-shear. EC preincubation with the antioxidant N-acetylcysteine (NAC; 20 mM for 2 h) completely abolished the shear-induced O2(-.) production and significantly inhibited ICAM-1 expression. EC preincubation with D-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP), an inhibitor of the GSL glycosyltransferases GlcT-1 and GalT-2, abrogated the shear-induced activation of GalT-2. D-PDMP also abolished the shear-induced O2(-.) production and ICAM-1 expression. We conclude that laminar shear stress activates GalT-2 to produce LacCer. In turn, LacCer activates NADPH oxidase, which produces O2(-.), and O2(-.) mediates the shear-induced increase in ICAM-1 expression. Thus, LacCer may play an important role in hemodynamic force-induced pathological conditions, such as atherosclerosis and ischemia/reperfusion injury.
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PMID:Lactosylceramide mediates shear-induced endothelial superoxide production and intercellular adhesion molecule-1 expression. 1174 Jan 54

Pro-rich antimicrobial peptides are a group of linear peptides of innate immunity isolated from mammals and invertebrates, and characterised by a high content of proline residues (up to 50%). Members of this group are predominantly active against Gram-negative bacterial species which they kill by a non-lytic mechanism, at variance with the majority of the known antimicrobial peptides. Evidence is accumulating that the Pro-rich peptides enter the cells without membrane lysis and, once in the cytoplasm, bind to, and inhibit the activity of specific molecular targets essential to bacterial growth, thereby causing cell death. This mode of action makes these peptides suitable for drug development efforts. In addition to antibacterial action, PR-39, one of the better characterised Pro-rich peptides from mammals, exerts other potentially exploitable biological activities, such as induction of syndecan expression in mesenchymal cells and inhibition of the NADPH oxidase activity of neutrophils, suggesting a role of this peptide in wound repair and inflammation. PR-39 also exerts a protective effect in various animal models of ischemia-reperfusion injury, preventing the post-ischemic oxidant production, and is a potent inducer of angiogenesis both in vitro and in vivo. Although the physiological relevance of all these effects has not yet been established, the above observations underscore the therapeutic potential of this peptide in a number of complex processes such as inflammation, wound repair, ischemia-reperfusion injury, and angiogenesis.
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PMID:Pro-rich antimicrobial peptides from animals: structure, biological functions and mechanism of action. 1194 70

We have shown previously that ischemia in an isolated rat lung that is normally oxygenated by continued ventilation results in lipid and protein oxidation, indicating the generation of reactive oxygen species. By using a variety of biochemical and imaging techniques, we determined that the initial response, which occurs within the first second of ischemia, is partial depolarization of the endothelial cell plasma membrane. This event is followed within several seconds by activation of endothelial NADPH oxidase and generation of superoxide anion at the extracellular surface of the cell membrane where it is dismutated to freely diffusible H2O2. Approximately 15 secs after the onset of ischemia, we detected an elevation of intracellular Ca2+ caused by its release from intracellular stores, followed by Ca2+ influx, possibly through T-type voltage-dependent Ca2+ channels. Increased nitric oxide generation through activation of endothelial nitric oxide synthase is detected after about 45 secs of ischemia. These changes (endothelial membrane depolarization, reactive oxygen species production, elevation of intracellular Ca2+ levels, and nitric oxide generation) were confirmed in isolated endothelial cells that had been adapted to shear stress in vitro. The in vitro model also demonstrates reactive oxygen species-dependent activation of nuclear factor-kappaB and activator protein-1 and that 24 hrs of ischemia results in increased cell division. These results indicate a novel cell-signaling pathway in response to loss of shear stress. The basis for these changes in endothelial function is related to mechanotransduction, i.e., altered shear stress rather than a metabolic response to ischemia. The biological function for the response may be an attempt to restore blood flow through vasodilatation and new capillary formation.
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PMID:Shear stress and endothelial cell activation. 1200 35

Under ischemic conditions, the vessel wall recruits inflammatory cells. Human aortic endothelial cells (HAECs) exposed to hypoxia followed by reoxygenation produce monocyte chemoattractant protein-1 (MCP-1); however, most experiments have been performed in the presence of nutrient deprivation (ND). We hypothesized that ND rather than hypoxia mediates endothelial MCP-1 production during ischemia, and that the small GTP-binding protein Rac1 and reactive oxygen species (ROS) are involved in this process. ND was generated by shifting HAECs from 10% to 1% FBS. Superoxide production by HAECs was increased 6 to 24 hours after ND, peaking at 18 hours. MCP-1 production was increased over a similar time frame, but peaked later at 24 hours. These effects were blocked by treatment with antioxidants such as superoxide dismutase mimetic and N-acetylcysteine (NAC), or NADPH oxidase inhibitors, DPI and gp91ds-tat. Superoxide and MCP-1 production were enhanced by RacV12 (constitutively active) in the absence of ND, and were inhibited by RacN17 (dominant-negative) adenoviral transduction under ND, suggesting that the small G-protein Rac1 is required. In conclusion, ND, an important component of ischemia, is sufficient to induce MCP-1 production by HAECs, and such production requires a functional Rac1, redox-dependent pathway.
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PMID:Rac-dependent monocyte chemoattractant protein-1 production is induced by nutrient deprivation. 1241 94

The objective of this study was to define the relationship among Kupffer cells, O(2)(-) production, and TNF-alpha expression in the pathophysiology of postischemic liver injury following short and long periods of ischemia. Using different forms of superoxide dismutase with varying circulating half-lives, a monoclonal antibody directed against mouse TNF-alpha, and NADPH oxidase-deficient mice, we found that 45 or 90 min of partial (70%) liver ischemia and 6 h of reperfusion (I/R) produced time-dependent increases in liver injury and TNF-alpha expression in the absence of neutrophil infiltration. Furthermore, we observed that hepatocellular injury induced by short periods of ischemia were not dependent on formation of TNF-alpha but were dependent on Kupffer cells and NADPH oxidase-independent production of O(2)(-). However, liver injury induced by extended periods of ischemia appeared to require the presence of Kupffer cells, NADPH oxidase-derived O(2)(-), and TNF-alpha expression. We conclude that the sources for O(2)(-) formation and the relative importance of TNF-alpha in the pathophysiology of I/R-induced hepatocellular injury differ depending on the duration of ischemia.
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PMID:Regulation of postischemic liver injury following different durations of ischemia. 1244 15

The aim of this study was to quantify the expression of E-selectin, intercellular cell adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) in human umbilical vascular endothelial cells (HUVECs) exposed to anoxia/reoxygenation (A/R) in the presence or absence of an inflammatory context (0.1 IU/ml tumor necrosis factor-alpha [TNF-alpha]) and to investigate the effects of two different NADPH inhibitors, apocynin and diphenyleneiodonium (DPI), on the expression of the endothelial cell adhesion molecules. Confluent HUVECs were exposed to anoxia for 3 hours (100% N2), followed by a reoxygenation period of 4 hours. TNF-alpha at 0.1 IU/ml was added to the medium either under normoxic conditions for 7 hours (TNF-alpha) or just before the start of anoxia (A/R + TNF-alpha). Levels of E-selectin, VCAM-1, and ICAM-1 were quantified using specific monoclonal antibodies revealed by an alkaline phosphatase-labeled goat F(ab)'2 fragment against mouse IgG antibody and the fluorescent substrate Attophos. Adhesion experiments were also performed using calcein-labeled U937 leukocytes. HUVECs submitted to A/R overexpressed E-selectin but not VCAM-1 or ICAM-1, whereas TNF-alpha at 0.1 IU/ ml increased the expression of all three adhesion molecules. In endothelial cells subjected to A/R in the presence of TNF-alpha, a synergistic increase of E-selectin expression and a synergistic adhesion of U937 cells was noted. The NADPH oxidase inhibitors apocynin and DPI both decreased significantly the U937 adhesion and the E-selectin overexpression on HUVECs submitted to A/R, TNF-alpha, or A/R + TNF-alpha. These results suggest that E-selectin expression is implicated in the leukocyte adhesion to HUVECs caused by A/R in the presence or absence of an inflammatory context. NADPH oxidase appears to participate in the E-selectin overexpression on HUVECs subjected either to A/R and/or TNF-alpha, suggesting a major role of this enzyme in the ischemia/reperfusion syndrome.
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PMID:Effect of NADPH oxidase inhibition on E-selectin expression induced by concomitant anoxia/reoxygenation and TNF-alpha. 1257 57

These studies using both intact lung and reconstituted cell systems have shown that pulmonary endothelial cells respond rapidly (within several seconds) to the acute cessation of perfusate flow, i.e., ischemia. These effects represent a response to the loss of shear stress and are unrelated to changes in cellular oxygenation. The immediate response is partial depolarization of the endothelial cell membrane followed by activation of endothelial NADPH oxidase and the extracellular generation of superoxide anion. Dismutation of superoxide to H2O2 generates a cell signaling molecule that results in the activation of protein kinases and transcription factors which in turn lead to NO generation and activation of endothelial cell division. The presumed physiological role of this signal cascade is the generation of a vasodilator (NO) and the formation of new capillaries in the effort to restore blood flow.
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PMID:Lung ischemia: endothelial cell signaling by reactive oxygen species. A progress report. 1258 Apr 51

The role of angiotensin II in myocardial ischaemia-reperfusion is not clearly defined. In this respect, the involvement of NADPH oxidase remains to be determined. The aim of this study was 1) to evaluate the cardiac effects of angiotensin AT(1) receptor stimulation in non-ischaemic conditions of perfusion or during ischaemia-reperfusion, and 2) to measure the concomitant activation of NADPH oxidase in isolated rat hearts perfused with angiotensin II and/or Losartan. In non-ischaemic hearts, angiotensin II induced rapid and prolonged vasoconstrictive and negative inotropic effects. Ischaemia-reperfusion increased the mRNA expression of AT(1) and AT(2) receptors. During reperfusion, angiotensin II reduced the incidence of arrhythmias and the lactate dehydrogenase released, and increased NADPH oxidase mRNA expression and enzyme activity. Losartan co-administration totally antagonised the effects of angiotensin II. Our study demonstrates that ischaemia-reperfusion induces adaptative cardiac modifications, which allow exogenously added angiotensin II to stimulate myocardial NADPH oxidase through angiotensin AT(1) receptor activation.
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PMID:Angiotensin II activates NADPH oxidase in isolated rat hearts subjected to ischaemia-reperfusion. 1259 Nov 7

Although hypercholesterolemia is widely accepted as a major risk factor for coronary artery and peripheral vascular diseases, its role in the pathogenesis of stroke is controversial. The objectives of this study were to determine how hypercholesterolemia affects the cerebral microcirculation under resting conditions and after ischemia-reperfusion (I/R). Platelet- and leukocyte-endothelial cell interactions and oxidant production (using the oxidant-sensitive fluorochrome dihydrorhodamine-123) were monitored by intravital videomicroscopy in the cerebral microvasculature of mice placed on either a normal (ND) or cholesterol-enriched diet (HCD). Platelets labeled with carboxyfluorescein diacetate succinimidyl ester (CFDASE) and leukocytes labeled with rhodamine 6G were seen to roll and firmly adhere, with a corresponding increase in oxidant production, in venules of mice on HCD, but not ND. Immunoneutralization of P-selectin attenuated the platelet- and leukocyte-endothelial cell interactions and the enhanced oxidant production associated with HCD. A GPIIb/IIIa blocking antibody did not alter the blood cell-vessel wall interactions to HCD. Mice deficient in the NADPH oxidase subunit gp91(phox) exhibited significantly blunted platelet and leukocyte recruitment responses to HCD. Focal I/R also elicited inflammatory and prothrombogenic responses in cerebral venules and these were exaggerated in mice on HCD. These results implicate an oxidant-dependent, P-selectin-mediated mechanism in the blood cell-vessel wall interactions induced by hypercholesterolemia in the brain and demonstrate that the deleterious effects of I/R on the brain are exacerbated by this cardiovascular risk factor.
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PMID:Cerebral microvascular responses to hypercholesterolemia: roles of NADPH oxidase and P-selectin. 1467 Aug 46

Adenosine plays a major cytoprotective role during ischemia and conditions of oxidative stress. Previous studies in our laboratory indicate that oxidative stress induces expression of the A1 adenosine receptor (A1AR) via activation of nuclear factor (NF)-kappaB. In this study, we tested whether noise exposure could induce oxidative stress and determine whether this induces expression of the A1AR in the chinchilla cochlea. Chinchillas were exposed to a 96 dB 4 kHz octave band of noise for 6 h of daily exposure, followed by an 18 h noise-free period. This noise paradigm resulted in threshold shifts of 10-60 dB over the frequency range (1-16 kHz) tested. Radioligand binding studies for the A1AR indicate a significant increase in receptor ( approximately 2-fold) expression soon after the first noise exposure period (usually within approximately 8 h of the initiation of noise), which gradually returned to basal levels by day 7. The rise in A1AR levels was followed by a significant increase in malondialdehyde levels by day 3, which also recovered by day 7. Assessment of the activity of NADPH oxidase in the cochlea indicates a significant increase in enzyme activity which was evident by approximately 8 h following initiation of noise exposure, and which persisted for at least up to day 3. Electrophoretic mobility shift assays indicate that the increase in A1AR was associated with a significant increase in NF-kappaB activity following noise exposure. We conclude that noise exposure induces A1AR expression, which might be mediated, in part, through generation of reactive oxygen species and activation of NF-kappaB.
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PMID:Noise induces A1 adenosine receptor expression in the chinchilla cochlea. 1475 70


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