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)

Ethanol is known to cause both tolerance and sensitization to endotoxin (lipopolysaccharide). It is also known that ethanol modulates the expression and activity of several intracellular signaling molecules and transcription factors in monocytes and Kupffer cells, the resident hepatic macrophages. Expression of CD14, the endotoxin receptor, is up-regulated following chronic exposure to endotoxin and ethanol. Ethanol-induced oxidative stress is important in the regulation of transcription factor activation and cytokine production by Kupffer cells. Thus, it was hypothesized that acute ethanol increases CD14 expression through a mechanism dependent upon oxidant production. This hypothesis was tested by overexpression of superoxide dismutase via recombinant adenovirus. Mice were infected with adenovirus (3 x 10(9) plaque-forming units, intravenously) containing either Cu,Zn superoxide dismutase (Ad.SOD1) or beta-galactosidase (Ad.lacZ), which caused significant expression of Cu,Zn-SOD in hepatocytes and Kupffer cells. Three days post-infection, mice were given saline or ethanol (5 g/kg, intragastrically). A significant increase in CD14 mRNA was observed 3 h after ethanol, and this increase was almost completely blocked in mice overexpressing Cu,Zn-SOD. Additionally, overexpression of SOD also blunted ethanol-induced activation of redox-sensitive transcription factors NFkappaB and AP-1 and production of cytokines. However, only inhibition of AP-1 with dominant-negative TAK1 but not NFkappaB by dominant-negative IkappaBalpha significantly blunted ethanol-induced increases in CD14, suggesting that AP-1 is important for CD14 transcriptional regulation. It is also shown here that NADPH oxidase is important in the increase in CD14 due to ethanol. Moreover, these data suggest that acute ethanol causes sensitization to endotoxin through mechanisms dependent upon oxidative stress.
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PMID:Up-regulation of CD14 in liver caused by acute ethanol involves oxidant-dependent AP-1 pathway. 1248 56

Oxidized lipids, such as 13-hydroperoxyoctadecadienoic acid (13-HPODE), have been implicated in the pathogenesis of atherosclerosis. 13-HPODE, a constituent of oxidized low-density lipoproteins, can induce cytotoxicity of vascular smooth muscle cells (SMC), which may facilitate plaque destabilization and/or rupture. 13-HPODE-induced cytotoxicity has been linked to oxidative stress, although the mechanisms by which this occurs are unknown. In the present study, we show that 13-HPODE and 9-HPODE (10-30 microM) increased superoxide (O2*-) production and induced cytotoxicity in SMC. The 13-HPODE-induced increase in O2*- was blocked by transfecting the cells with antisense oligonucleotides against p22phox, suggesting that the O2*- was produced by NAD(P)H oxidase. Similar concentrations of the corresponding HPODE reduction products, 13-hydroxyoctadecadienoic acid (13-HODE) and 9-HODE, neither increased O2*- production nor induced cytotoxicity, while 4-hydroxy nonenal (4-HNE), an unsaturated aldehyde lipid peroxidation product, induced cytotoxicity without increasing O2*- production. Treatment with superoxide dismutase or Tiron to scavenge O2*-, or transfection with p22phox antisense oligonucleotides to inhibit O2*- production, attenuated 13-HPODE-induced cytotoxicity, but not that induced by 4-HNE. These findings suggest that activation of NAD(P)H oxidase, and production of O2*-, play an important role in lipid hydroperoxide-induced smooth muscle cytotoxicity.
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PMID:Activation of NAD(P)H oxidase by lipid hydroperoxides: mechanism of oxidant-mediated smooth muscle cytotoxicity. 1265 83

Although hypertension is a major risk factor for atherosclerosis, its underlying mechanisms remain to be delineated. We have recently reported that both endothelin-1 (ET-1) and vascular cellular adhesion molecule-1 (VCAM-1) levels, key early markers of atherosclerosis, are significantly elevated in carotid arteries of deoxycorticosterone acetate (DOCA)-salt hypertensive rats, a model known for its suppressed plasma renin levels. This study tested the hypothesis that ET-1 augments arterial VCAM-1 expression through NADPH oxidase-derived superoxide (O2-). Carotid arteries of DOCA-salt or sham-operated rats were transduced ex vivo with extracellular superoxide dismutase (EC-SOD), dominant negative HA-tagged N17Rac1 that inhibits Rac1, the small GTPase component of NADPH oxidase, or beta-galactosidase (beta-gal) reporter gene (5x10(10) plaque formation units [pfu]/mL), and the effect of transgene expression on O2- and VCAM-1 levels was assayed 24 hours afterward. The arterial activity of NADPH oxidase but not xanthine oxidase was significantly higher in DOCA-salt than in sham rats, which was abolished by the selective ETA receptor antagonist ABT-627 (3x10(-8) mol/L), NADPH oxidase inhibitor apocynin (10(-4) mol/L), or dominant negative Rac1 gene transfer. The levels of O2- and VCAM-1 were significantly increased in arteries of DOCA-salt rats, an effect that was ameliorated after EC-SOD or dominant negative Rac1 but not beta-gal reporter gene transfer. ABT-627 and apocynin also significantly reduced elevated VCAM-1 levels in ET-1-treated arteries of normal rats and arteries of DOCA-salt rats. The results of this study indicate that ET-1 stimulates arterial VCAM-1 expression by producing O2- from an ETA receptor/NADPH oxidase pathway in low-renin mineralocorticoid hypertension.
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PMID:Endothelin-1 stimulates arterial VCAM-1 expression via NADPH oxidase-derived superoxide in mineralocorticoid hypertension. 1451 26

Overproduction of reactive oxygen species or increased oxidative stress is considered a major mechanism involved in the pathogenesis of endothelial dysfunction, the initiation and progression of atherosclerosis and its adverse events. Evidence supports the importance of nitric oxide derived from endothelial nitric oxide synthase as a vasoprotective substance, and of vascular NAD(P)H oxidase-derived reactive oxygen species as important signaling molecules in vascular cells. Recent studies show that dysfunction of endothelial nitric oxide synthase in atherosclerosis generates O(2)(-) rather than nitric oxide, and that upregulation of vascular NAD(P)H oxidase is closely associated with atherosclerotic progression and plaque instability.
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PMID:Oxidant stress and atherosclerosis. 1506 53

Proliferation of endothelial cells plays a crucial role in the process of atherosclerotic plaque destabilization. The major component of oxidized low-density lipoprotein lysophosphatidylcholine (LPC) has been shown to promote endothelial proliferation by increasing the production of reactive oxygen species (ROS). Since K(+) channels are known to control the cell cycle, we investigated the role of Ca(2+)-activated K(+) channels (BK(Ca)) in the regulation of LPC-induced endothelial proliferation and ROS generation. A significant increase of cell growth induced by LPC (20 micromol/l; cell counts (CCs): +87%, thymidin incorporation: +89%; n = 12, P < 0.01) was observed, which was inhibited by the BK(Ca) inhibitor iberiotoxin (IBX; 100 nmol/l), by the NAD(P)H-oxidase inhibitor diphenyleneiodonium (5 micromol/l) and by transfection with antisense (AS) oligonucleotides against NAD(P)H oxidase, whereas N(G)-monomethyl-l-arginine (l-NMMA) further increased LPC-induced cell growth. Using the patch-clamp technique a significant increase of BK(Ca) open-state probability (control: 0.004 +/- 0.002; LPC: 0.104 +/- 0.035; n = 21, P < 0.05) by LPC was observed. Using dichlorofluorescein fluorescence microscopy a significant increase of ROS induced by LPC was reported, that was blocked by IBX and Ca(2+) antagonists. Intracellular Ca(2+) measurements revealed a capacitative Ca(2+) influx caused by LPC. Bioactivity of nitric oxide (NO) was measured using a [(3)H]-cGMP radioimmunoassay. LPC significantly decreased acetylcholine-induced NO synthesis. LPC significantly increased cGMP levels in endothelial cells transfected with AS, which was blocked by IBX. In conclusion, our results demonstrate that LPC activates BK(Ca) thereby increasing ROS production which induces endothelial proliferation. In addition LPC-induced BK(Ca)-activation contributes to increased cGMP levels, if ROS production is prevented by AS.
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PMID:Lysophosphatidylcholine-induced modulation of Ca(2+)-activated K(+)channels contributes to ROS-dependent proliferation of cultured human endothelial cells. 1513 62

Of the many symposia at the 28th World Congress of the International Society of Heart Research, held August 7-10, 2004, in Queensland, Australia, this report covers the following: understanding the basic mechanisms of cardiac arrhythmias; unstable plaque; innate immunity in cardiovascular health and disease; matrix metalloproteinases; defining the targets for treatment of heart failure; NAD(P)H oxidase-derived reactive oxygen species--signaling or stress; expanding roles for alpha(1)-adrenoceptors in the cardiovascular system; estrogen derivatives in cardiovascular disease--old questions, new answers; and p38 MAPK: a kind or callous kinase. Lectures on the use of gene therapy for cardioprotection and antiarrhythmic actions of calmodulin kinase inhibition, and selected poster presentations are also discussed.
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PMID:Recent advances in heart research. 1575 77

Our previous study demonstrated that homocysteine (Hcy) mediated the expression and secretion of MCP-1 and IL-8 in human monocytes. In the present study, we investigated whether the responsiveness of isolated monocytes to lipopolysaccharide (LPS)-induced chemokine secretion was enhanced in patients with hyperhomocysteinemia (HHcy), and if so, whether this enhanced response could be inhibited by folic acid treatment. We studied 38 control subjects and 40 patients with HHcy. The results showed that MCP-1 secretion from isolated monocytes in response to low-dose LPS in patients with HHcy was significantly higher than that in controls. After patients with HHcy underwent low-dose folic acid treatment (0.8 mg/d) for 6 months, plasma Hcy levels were decreased and the hyper-responsiveness of MCP-1 and IL-8 secreted by isolated monocytes was significantly reversed. Furthermore, folic acid treatment at high concentrations (5 microM) significantly reduced the elevated levels of reactive oxygen species, NADPH oxidase activity and chemokines in response to Hcy in cultured human monocytes. HHcy may contribute to atherogenesis through enhancing the responsiveness of monocytes to inflammatory stimuli and promoting leukocyte recruitment into atherosclerotic plaque. In addition to lowering the plasma levels of Hcy, low-dose folic acid treatment exerts beneficial effects on patients with HHcy by inhibiting pro-inflammatory responses such as chemokine secretion from human monocytes.
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PMID:Folic acid reverses hyper-responsiveness of LPS-induced chemokine secretion from monocytes in patients with hyperhomocysteinemia. 1577 59

Previous data have indicated that modification of proteins/lipids by glucoxidation and/or lipid oxidation may initiate/propagate the formation of atherosclerotic plaques. Although the biomarker carboxymethyllysine (CML) has been detected in these lesions, the origin of the reactive oxygen species (ROS) leading to its formation and the source of its carbon backbone are unknown. As presented here, the stimulation of cultured monocytes by phorbol-12-myristate-13-acetate (TPA), an activator of protein kinase C that can mimic the effects of high glucose, angiotensin II, and other physiological stimuli, leads to cellular ROS generation and concomitant formation of intracellular CML. Inhibitors of ROS-generating cellular systems such as NO synthase, xanthine oxidase, or cytochrome P450 oxidase had no effect on CML formation. Likewise, in cells with inactive NAD(P)H oxidase no reduced CML formation was found. In cells exhibiting a high glycolysis rate, CML formation was unaffected. Because we found rapid CML formation in the presence of unsaturated fatty acids, it appears that lipid oxidation is quantitatively more important. In vivo studies revealed strong intracellular CML staining in areas of histiocytic/monocytic infiltration or proliferation, mostly associated with atheroma formation. Corresponding CML staining patterns were found in healing wounds of different ages, indicating that formation of atherosclerosis is a chronic wound repair associated with a low-grade inflammatory reaction. In summary, CML is formed concomitantly with oxidative stress in activated monocytes and can be regarded as a biomarker for a low-grade inflammatory tissue reaction in the atherosclerotic plaque. Its formation via lipid oxidation may be involved in the development of atherosclerosis.
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PMID:Role of glucoxidation and lipid oxidation in the development of atherosclerosis. 1603 56

C-reactive protein (CRP) is a powerful predictor and risk factor for cardiovascular diseases. The CXC- and CC-type chemokines interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) are important chemokines for leukocyte trafficking identified in atheromatous plaque expressed mainly by macrophages in humans. We assessed whether C-reactive protein could induce MCP-1 and IL-8 secretion. In human peripheral blood monocytes, C-reactive protein (12.5-50 microg/mL) increased IL-8, but not MCP-1 secretion in a time- (6-24 hours) and dose-dependent manner as detected by ELISA. C-reactive protein could augment the production of reactive oxygen species (ROS) as measured by chemiluminescence and inhibitors of NAD(P)H oxidase (DPI and PAO) and ROS scavengers (superoxide dismutase, catalase, and 1% dimethyl sulphoxide) abolished C-reactive protein-induced IL-8 secretion. Furthermore, relative quantity of IL-8 mRNA was significantly increased by C-reactive protein 50 microg/mLfor 12 hours, which could be inhibited by DPI 1 microM or superoxide dismutase (SOD) 250 U/mL. The inhibitors of ERK 1/2 (PD98059), p38 (SB203580) MAPK, and NF-kappaB (PDTC and MG132) significantly decreased C-reactive protein-induced IL-8 secretion in human monocytes. Also, agonists of peroxisome proliferator-activated receptor (PPAR) alpha (WY14643) and PPARgamma (troglitazone) could largely inhibit C-reactive protein responses. Thus, our data indicate that C-reactive protein at pathologic levels increases IL-8 secretion and mRNA via enhancing ROS derived mainly from NAD(P)H oxidase and the subsequent activation of ERK1/2, p38 MAPK, and NF-kappaB. The activation of PPARalpha/gamma can negatively regulate C-reactive protein-induced IL-8 production in human monocytes.
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PMID:C-reactive protein augments interleukin-8 secretion in human peripheral blood monocytes. 1622 77

They were more than just another kinases (JAK), when they were first described in the late 80s and named JAK kinases. The mandatory role of this novel family of dual active janus kinases (JAK) and their substrates the signal transducers and activators of transcription (STAT) was demonstrated in mice who died during embryogenesis when lacking a functional allele, e.g. that of JAK2. Initially, the JAK/STAT signaling pathway was discovered as the primary mediator of intracellular signaling induced by interferon in hematopoietic and immune cells. Nowadays, it is well accepted that JAK kinases and STAT proteins are constitutively expressed in the vessel wall in a cell type specific manner and transfer intracellular signaling events of various receptor families, e.g. that of cytokines, growth factors and vasoactive peptides such as angiotensin II (Ang II) or endothelin. The potential impact of the JAK/STAT signaling pathway on cardiovascular pathophysiology and disease development arise from reports describing that JAKs may bind directly to the angiotensin II type I (AT(1)) receptor, thereby enhancing their phosphorylation in various cell types of the vessel wall. More interestingly, these signaling events are modulated by NAD(P)H oxidase-derived superoxide anions which directly phosphorylate JAK2 and thereby control JAK2 activity. A potential impact was also described for atherosclerotic plaque development in which the activation of JAKs and STATs seems to be critical. Based on these observations, we here review the role of the JAK/STAT signaling pathways as critical regulator for cardiovascular disease development, i.e. atherosclerotic plaque progression or the manifestation of arterial hypertension.
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PMID:JANUS under stress--role of JAK/STAT signaling pathway in vascular diseases. 1627 17


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