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)

Proteinase 3 (PR3), the target autoantigen of antineutrophil cytoplasmic antibodies in the autoimmune vasculitis, Wegener's granulomatosis, is a serine proteinase stored in granules of human neutrophils. PR3 is expressed also on the plasma membrane of unactivated neutrophils, and this expression increases in primed or stimulated cells. In the current study, we demonstrate the presence of PR3, FcgammaRIIIb, and cytochrome b558 of the NADPH oxidase in neutrophil lipid rafts. Activation of neutrophils with PMA, fmet-leu-phe, or TNFalpha known to increase the membrane expression of PR3 did not affect the amount of PR3 in rafts. Unexpectedly, the cytosolic subunits of the NADPH oxidase, p67phox and p47phox, the recruitment of which to the membrane requires cell stimulation, were detected in the rafts of unstimulated neutrophils. Treatment of neutrophils with the cholesterol-sequestering agent methyl-beta-cyclodextrin (MbetaCD) reduced raft p22phox and PR3. MbetaCD diminished membrane FcgammaRIIIb upregulating membrane PR3 (mPR3) and CD11b/CD18. In addition, MbetaCD significantly reduced PMA-induced activity of the NADPH oxidase without altering fmet-leu-phe-elicited activity. Antibody-mediated cross-linking of membrane PR3 caused activation of ERK and JNK kinases and their translocation to rafts. Confocal analysis revealed colocalization of mPR3, FcgammaRIIIb, and p22phox in the membrane, confirmed by their coimmunoprecipitation. Cleavage of neutrophil GPI-anchors by PI-PLC reduced mPR3 and FcgammaRIIIb, implicating a GPI-protein, possibly FcgammaRIIIb, in the attachment of PR3 to the membrane.
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PMID:The presence of membrane Proteinase 3 in neutrophil lipid rafts and its colocalization with FcgammaRIIIb and cytochrome b558. 1591 59

Monocyte chemotactic protein-1 (MCP-1), a potent chemoattractant for monocytes, is thought to play a major role in atherosclerosis, but whether its atherogenic effects involve the direct modulation of vascular smooth muscle cell (SMC) functions remains unclear. This study examined the effects of MCP-1 on the migration of cultured A7r5 SMCs and the signaling pathways involved. Addition of recombinant MCP-1 stimulated SMC migration in modified Boyden chambers coated with type I collagen in a concentration-dependent manner, with 10(-9) M being maximally effective. Using untreated A7r5 cells, two MCP-1 receptors, CCR2 and CCR4, were detected and MCP-1 secretion was significantly increased by stimulation with platelet-derived growth factor. MCP-1-stimulated A7r5 migration was completely blocked by the NAD(P)H oxidase inhibitor, diphenylene iodonium (DPI), and dose-dependently inhibited by polyethylene glycol-conjugated superoxide dismutase (PEG-SOD), suggesting a role for reactive oxygen species (ROS) in this process. During MCP-1 stimulation, ROS production increased rapidly, then gradually decayed over 60 min, and this effect was markedly decreased by pretreatment with DPI or PEG-SOD. Interestingly, U0126 and PD98059, which inhibit activation of extracellular signal-regulated kinases 1/2 (ERK 1/2), significantly inhibited MCP-1-activated ROS generation. Furthermore, transfection of an active mutant of MEK1 (ERK 1/2 kinase) markedly increased superoxide production in rat aortic smooth muscle cells, as detected by dihydroethydium staining, suggesting that ERK 1/2 activation stimulates ROS generation. ERK 1/2 activation was increased for at least 30 min in cells incubated with MCP-1, and this effect was abolished by U0126 or DPI pretreatment. These results demonstrate that MCP-1 is a chemoattractant for SMCs and that MCP-1-stimulated migration requires both ROS production and ERK 1/2 activation in a positive activation loop, which may contribute to the atherogenic effects of MCP-1.
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PMID:Reactive oxygen species and ERK 1/2 mediate monocyte chemotactic protein-1-stimulated smooth muscle cell migration. 1591 91

Matrix metalloproteinases (MMPs), aldosterone, and reactive oxygen species (ROS) are implicated in myocardial remodeling. Although ROS, cytokines, and neurohormones regulate MMP in cardiac fibroblasts, it is unknown whether aldosterone regulates MMP in cardiomyocytes. Therefore, we tested the hypothesis that aldosterone regulates MMP in cultured adult rat ventricular myocytes (ARVMs). ARVMs were treated with aldosterone for 24 hours, and MMP-2 and MMP-9 activities were measured by zymography. Aldosterone (50 nmol/L) increased MMP-2 (43+/-5%) and MMP-9 (55+/-15%; P<0.001 for both) activities. Pretreatment with spironolactone (100 nmol/L) abolished the aldosterone-induced increase in MMP activities. Aldosterone (50 nmol/L; 30 minutes) increased mitogen/extracellular signal-regulated kinase (MEK) (31+/-3%) and extracellular signal-regulated kinase 1/2 (ERK1/2; 41+/-7%; P<0.001 for both) phosphorylation. U0126 (10 micromol/L), an MEK1/2 inhibitor, abolished the aldosterone-induced increase in MMP activities. Aldosterone increased intracellular ROS as assessed by dichlorofluorescein diacetate (27+/-4%; P<0.05). This increase was inhibited by apocynin, an NADPH oxidase inhibitor. Apocynin likewise inhibited aldosterone-induced ERK1/2 phosphorylation and the increase in MMP activities. Furthermore, the antioxidants MnTMPyP and N-acetylcysteine inhibited the aldosterone-induced increase in ERK1/2 phosphorylation and MMP activities, respectively. Protein kinase C (PKC) is implicated in the nongenomic effects of aldosterone. To test the role of PKC, ARVMs were pretreated with chelerythrine, a PKC inhibitor. Chelerythrine prevented the aldosterone-induced increase in ERK1/2 phosphorylation and MMP activities. Thus, aldosterone induces MMP activity in ARVM via activation of the mineralocorticoid receptor, PKC, and ROS-dependent activation of the MEK/ERK pathway. NADPH oxidase is a likely source of ROS in this system.
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PMID:Aldosterone stimulates matrix metalloproteinases and reactive oxygen species in adult rat ventricular cardiomyocytes. 1604 62

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

Elevated levels of tumor necrosis factor-alpha (TNF), a proinflammatory cytokine, are associated with coronary artery disease. However, it is unclear whether vasodilator function of coronary resistance arterioles is susceptible to TNF. Herein, we examined whether TNF can affect endothelium-dependent nitric oxide (NO)-mediated dilation of coronary arterioles to adenosine and whether inflammatory signaling pathways such as mitogen-activated protein kinases, ceramide sphingolipids, and oxidative stress are involved in the TNF-mediated effect. To eliminate confounding influences associated with in vivo preparations, coronary arterioles from porcine heart were isolated and pressurized without flow for in vitro study. Intraluminal treatment with TNF (1 ng/ml, 90 min) significantly attenuated the NO release and vasodilation to adenosine. This inhibitory effect was not observed in denuded vessels or in the presence of NO synthase inhibitor l-NMMA. Histochemical data showed that superoxide production and JNK phosphorylation in arteriolar endothelial cells was enhanced by TNF. Administration of superoxide scavenger or inhibitors of ceramide-activated protein kinase (dimethylaminopurine), JNK (SP600125 and dicumarol), and xanthine oxidase (allopurinol) reduced superoxide production as well as restored NO release and vasodilation to adenosine. Conversely, the effects of TNF were insensitive to inhibitors of p38 (SB203580), ERK (PD98059), NAD(P)H oxidase (apocynin), or mitochondrial respiratory chain (rotenone). These data indicate that TNF inhibits endothelium-dependent NO-mediated dilation of coronary arterioles by ceramide-induced activation of JNK and subsequent production of superoxide via xanthine oxidase. Because myocardial ischemia augments adenosine production and elevates TNF level, inhibiting adenosine-stimulated endothelial release of NO by TNF could contribute to inadequate regulation of coronary blood flow during the development of ischemic heart disease.
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PMID:Activation of JNK and xanthine oxidase by TNF-alpha impairs nitric oxide-mediated dilation of coronary arterioles. 1641 74

Nuclear factor erythroid 2-related factor (Nrf2) confers protection against cell death induced by hyperoxia and other proapoptotic stimuli. Because phosphoinositide-3-kinase (PI3K)/Akt signaling promotes cell survival, the significance of this pathway in mediating reactive oxygen species (ROS)-dependent hyperoxia-induced Nrf2 activation was investigated in the murine pulmonary epithelial cell line, C10. Inhibition of the PI3K pathway markedly attenuated hyperoxia-induced Nrf2 translocation and ARE (antioxidant response element)-mediated transcription. Consistent with this, hyperoxia markedly stimulated the activation of PI3K pathway, while an NADPH oxidase inhibitor and an antioxidant prevented such activation. The inhibition of Akt activity using a pharmacological inhibitor markedly attenuated Nrf2 translocation and ARE-driven expression. Moreover, overexpression of a dominant-negative Akt mutant attenuated the transcription, whereas a constitutively active mutant stimulated it. These results suggest that PI3K/Akt signaling regulates Nrf2 activation by hyperoxia. Inhibition of the PI3K pathway prevented hyperoxia-stimulated Akt and ERK1/2 kinase activation, which is critical for Nrf2-mediated transcription. Likewise, the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, AG1478, blocked hyperoxia-stimulated Akt and ERK1/2 phosphorylation, Nrf2 nuclear accumulation, and ARE-driven transcription. Consistent with this result, an NADPH oxidase inhibitor blocked hyperoxia- stimulated EGFR phosphorylation, which was correlated with the attenuation of Akt and ERK activation. Collectively, our data suggest that EGFR-PI3K signaling through Akt and ERK kinases regulates ROS-dependent, hyperoxia-induced Nrf2 activation in pulmonary epithelial cells.
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PMID:Hyperoxia stimulates an Nrf2-ARE transcriptional response via ROS-EGFR-PI3K-Akt/ERK MAP kinase signaling in pulmonary epithelial cells. 1648 36

Although 2,4,6-trinitrotoluene (TNT) has been found to uncouple nitric oxide synthase (NOS), thereby leading to reactive oxygen species (ROS), cellular response against TNT still remains unclear. Exposure of bovine aortic endothelial cells (BAECs) to TNT (100 microM) resulted in serine 1179 phosphorylation of endothelial NOS (eNOS). With specific inhibitors (wortmannin and LY294002), we found that PI3K/Akt signaling participated in the eNOS phosphorylation caused by TNT, whereas the ERK pathway did not. ROS were generated following exposure of BAECs to TNT. However, TNT-mediated phosphorylation of either eNOS or Akt was drastically blocked by NAC and PEG-CAT. Interestingly, pretreatment with apocynin, a specific inhibitor for NADPH oxidase, diminished the phosphorylation of eNOS and Akt. These results suggest that TNT affects NADPH oxidase, thereby generating hydrogen peroxide, which is capable of activating PI3K/Akt signaling associated with eNOS Ser 1179 phosphorylation.
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PMID:Serine 1179 phosphorylation of endothelial nitric oxide synthase caused by 2,4,6-trinitrotoluene through PI3K/Akt signaling in endothelial cells. 1651 56

The matrix fibronectin protein plays an important role in vascular remodeling. Notoginsenoside R1 is the main ingredient with cardiovascular activity in Panax notoginseng; however, its molecular mechanisms are poorly understood. We report that notoginsenoside R1 significantly decreased TNF-alpha-induced activation of fibronectin mRNA, protein levels, and secretion in human arterial smooth muscle cells (HASMCs) in a dose-dependent manner. Notoginsenoside R1 scavenged hydrogen peroxide (H2O2) in a dose-dependent manner in the test tube. TNF-alpha significantly increased intracellular ROS generation and then ERK activation, which was blocked by notoginsenoside R1 or DPI and apocynin, inhibitors of NADPH oxidase, or the antioxidant NAC. Our data demonstrated that TNF-alpha-induced upregulation of fibronectin mRNA and protein levels occurs via activation of ROS/ERK, which was prevented by treatment with notoginsenoside R1, DPI, apocynin, NAC, or MAPK/ERK inhibitors PD098059 and U0126. Notoginsenoside R1 significantly inhibited H2O2-induced upregulation of fibronectin mRNA and protein levels and secretion; it also significantly inhibited TNF-alpha and H2O2-induced migration. These results suggest that notoginsenoside R1 inhibits TNF-alpha-induced ERK activation and subsequent fibronectin overexpression and migration in HASMCs by suppressing NADPH oxidase-mediated ROS generation and directly scavenging ROS.
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PMID:Notoginsenoside R1 inhibits TNF-alpha-induced fibronectin production in smooth muscle cells via the ROS/ERK pathway. 1663 26

The renin-angiotensin system is a central component of the physiological and pathological responses of cardiovascular system. Its primary effector hormone, angiotensin II (ANG II), not only mediates immediate physiological effects of vasoconstriction and blood pressure regulation, but is also implicated in inflammation, endothelial dysfunction, atherosclerosis, hypertension, and congestive heart failure. The myriad effects of ANG II depend on time (acute vs. chronic) and on the cells/tissues upon which it acts. In addition to inducing G protein- and non-G protein-related signaling pathways, ANG II, via AT(1) receptors, carries out its functions via MAP kinases (ERK 1/2, JNK, p38MAPK), receptor tyrosine kinases [PDGF, EGFR, insulin receptor], and nonreceptor tyrosine kinases [Src, JAK/STAT, focal adhesion kinase (FAK)]. AT(1)R-mediated NAD(P)H oxidase activation leads to generation of reactive oxygen species, widely implicated in vascular inflammation and fibrosis. ANG II also promotes the association of scaffolding proteins, such as paxillin, talin, and p130Cas, leading to focal adhesion and extracellular matrix formation. These signaling cascades lead to contraction, smooth muscle cell growth, hypertrophy, and cell migration, events that contribute to normal vascular function, and to disease progression. This review focuses on the structure and function of AT(1) receptors and the major signaling mechanisms by which angiotensin influences cardiovascular physiology and pathology.
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PMID:Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular system. 1687 Aug 27

RAW macrophages, which express the PDE4D3 and PDE4D5 cAMP phosphodiesterase isoforms, exhibited increased PDE4 activity when challenged with H2O2 in a fashion that was negated by treatment with the cell permeant antioxidant, N-acetyl cysteine and by diphenyleneiodonium chloride, an inhibitor of NADPH oxidase. In Cos1 cells transfected to express PDE4D3, challenge with H2O2 caused a rapid increase in both the activity and phosphorylation of PDE4D3. Lysates from H2O2-treated COS cells caused the phosphorylation of purified, recombinant PDE4D3 at two sites. One was the established ERK phosphorylation site at Ser579, located at the extreme C-terminus of the catalytic unit, and the other was a novel site at Ser239, located at the extreme N-terminus of the catalytic unit. Double Ser239Ala:Ser579Ala mutation of PDE4D3 prevented its H2O2-dependent phosphorylation both in vitro and in intact COS cells. Phosphorylation of PDE4D3 at Ser579 was ablated by treating COS cells with the MEK inhibitor, PD98059, which also negated activation. The activity of the Ser239Ala:Ser579Ala double mutant, and the Ser579Ala single PDE4D3 mutant was unaffected by H2O2 challenge of COS cells, whilst the Ser239Ala mutant was inhibited. Wortmannin inhibited the H2O2-dependent phosphorylation of PDE4D3 in COS cells by around 50%, whilst it fully ablated phosphorylation at Ser239 as well as ablating activation of PDE4D3. Neither immunodepletion of p70S6 kinase nor siRNA-mediated knockdown of mTor inhibited the H2O2-dependent phosphorylation of PDE4D3 at Ser239. Activation of PDE4D3 by challenge with H2O2 was not additive with activation through protein kinase A (PKA)-mediated phosphorylation of PDE4D3. Challenge with H2O2 did not alter PKA-mediated phosphorylation of PDE4D3 at Ser54. H2O2 dependent phosphorylation of PDE4D3, at Ser239 and Ser579, did not alter the sensitivity of PDE4D3 to inhibition by the selective PDE4 inhibitor, rolipram. An unknown protein kinase acting downstream of phosphatidyl inositol 3-kinase phosphorylates PDE4D3 at Ser239. This switches the effect of phosphorylation by ERK at Ser579 from inhibition to activation. We propose that phosphorylation at Ser239 attenuates interaction between either UCR2 or the UCR1/UCR2 module and the PDE4 catalytic unit so as to re-programme the functional outcome effect of phosphorylation by ERK. We identify a novel process through which reactive oxygen species activate long PDE4 isoforms so as to reduce cAMP levels and thereby promote inflammatory responses.
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PMID:Oxidative stress employs phosphatidyl inositol 3-kinase and ERK signalling pathways to activate cAMP phosphodiesterase-4D3 (PDE4D3) through multi-site phosphorylation at Ser239 and Ser579. 1697 30


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