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)

Endothelial cells (ECs) under hemodynamic forces increase intracellular reactive oxygen species (ROS) that modulate gene expression. We previously showed that NO attenuated the shear flow-induced gene level. The present study explored the role of endothelial NO in cyclic strain-treated ECs. Treatment of ECs with S-nitroso-N-acetylpenicillamine (SNAP), an NO donor, reduced cyclic strain-induced monocyte chemotactic protein (MCP)-1 expression. Conversely, exposure of ECs to an NO synthase inhibitor augmented MCP-1 mRNA levels. NO attenuated the binding of activator protein-1 to the 12-O-tetradecanoylphobol-13-acetate-responsive element (TRE) in the MCP-1 promoter region. ECs overexpressed with endothelial NO synthase (eNOS) inhibited cyclic strain-induced MCP-1 expression and MCP-1 promoter (-540 bp) activity. Consistently, ECs treated with SNAP or infected with adenovirus carrying eNOS reduced strain-induced superoxide levels. These strain-induced superoxide and MCP-1 expressions were greatly blunted by treating ECs with an NADPH oxidase inhibitor, diphenyleneiodonium chloride or apocynine, but not with a xanthine oxidase inhibitor. ECs infected with adenovirus carrying the dominant-negative mutant of Rac (RacN17), a component of NADPH oxidase, reduced the strain-induced superoxide and MCP-1 expression. In contrast, ECs transfected with a constitutively active Rac (RacV12) increased MCP-1 and 4x TRE promoter activities. However, ECs cotransfected with eNOS and RacV12 reduced those promoter activities. Consistently, the increases of superoxide levels and MCP-1 expression by overexpression of RacV12 were abolished after infecting ECs with eNOS. Our results show that NO from eNOS-inhibiting redox-sensitive MCP-1 expression is mediated via Rac-dependent NADPH oxidase by reducing ROS. This study provides a molecular basis to support the notion that endothelial NO acts as an antioxidant by negatively regulating redox-sensitive gene expression in ECs constantly under hemodynamic influence.
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PMID:NO modulates monocyte chemotactic protein-1 expression in endothelial cells under cyclic strain. 1174 68

Reactive oxygen species (ROS) play an important but not yet fully defined role in the expression of inflammatory genes such as monocyte chemoattractant protein (MCP)-1. We used complementary molecular and biochemical approaches to explore the roles of specific ROS and their molecular linkage to inflammatory signaling in endothelial cells. Adenovirus-mediated expression of superoxide dismutase and catalase inhibited TNF-alpha-induced MCP-1 gene expression, suggesting important roles of superoxide (O(2)(-).) and H(2)O(2) in MCP-1 gene activation. In addition, the iron chelator 1,2-dimethyl-3-hydroxypyridin-4-one and the hydroxyl radical scavengers dimethylthiourea and dimethyl sulfoxide inhibited TNF-alpha-induced MCP-1 expression, suggesting important roles of iron and hydroxyl radicals in inflammatory signal activation. In contrast, scavenging of peroxynitrite with 5,10,15,20-tetrakis-(4-sulfonatophenyl)prophyrinato iron (III) chloride had no effect on TNF-alpha-induced MCP-1 expression. Inhibition of NADPH oxidase, the major oxidase responsible for O(2)(-). generation, with diphenylene iodonium suppressed TNF-alpha-induced MCP-1 mRNA accumulation. Rac1 is an upstream signaling molecule for the activation of NADPH oxidase and O(2)(-). generation. Expression of dominant negative N17Rac1 by adenovirus suppressed TNF-alpha-induced MCP-1 mRNA levels and MCP-1 protein secretion. Expression of N17Rac1 inhibited TNF-alpha-induced MCP-1 and NF-kappaB transcriptional activity. These data suggest that ROS such as superoxide and H(2)O(2) derived from Rac1-activated NADPH oxidase mediate TNF-alpha-induced MCP-1 expression in endothelial cells.
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PMID:Superoxide, H2O2, and iron are required for TNF-alpha-induced MCP-1 gene expression in endothelial cells: role of Rac1 and NADPH oxidase. 1457 80

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

AT(1) double receptor (AT(1A) and AT(1B)) knockout mice have lower blood pressure, impaired growth, and develop early renal microvascular disease and tubulointerstitial injury. We hypothesized that there would be an increased expression of vasoactive, profibrotic, and inflammatory mediators expressed in the kidneys of AT(1) double-knockout mice. We examined the renal expression of various mediator systems in control (n = 6) vs. double-knockout mice (n = 6) at 3-5 mo of age by real-time PCR, immunohistochemistry, and Western blot analysis. AT(1) double-knockout mice show activation of Th1-dependent pathways (with increased expression of IFN-alpha, IL-2 mRNA) with increased expression of both monocyte (MCP-1 mRNA) and T cell (RANTES mRNA) chemokines, infiltration of CD4(+) and CD11b(+) cells, increased fibrosis-associated mediators (CTGF, TGF-beta and TNF-alpha mRNA) and extracellular matrix (collagens I and III mRNA and protein) deposition compared with controls (P < 0.05 for all markers). These changes were associated with increased mRNA expression of endothelin (ET)-1 and ET-A receptor (P < 0.05), cyclooxygenase (COX)-2/TXA2 synthase (P < 0.05), NADPH oxidase (p40-phox, p67-phox, P < 0.05) and iNOS and nNOS (P < 0.05). COX-2 and nNOS protein were also increased in the kidneys of AT(1) double-knockout mice by Western blot analysis (P < 0.05). Although renin and angiotensinogen mRNA expression were increased in the knockout mice, AT(2) receptor mRNA expression was not significantly different from wild-type mice. In conclusion, the absence of the AT(1) receptor is associated with marked renal alterations in vasoactive, profibrotic, and immune mediators with an inflammatory pattern favoring a Th1 phenotype.
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PMID:Th1 inflammatory response with altered expression of profibrotic and vasoactive mediators in AT1A and AT1B double-knockout mice. 1592 10

Adrenomedullin (AM), a potent vasodilator peptide, has recently been suggested to function as an endogenous antioxidant. However, its potential site of action at the cellular level has not been clarified. The present study was undertaken to investigate whether AM directly inhibits intracellular reactive oxygen species (ROS) generation and redox-sensitive gene expression stimulated by angiotensin (Ang) II in rat aortic endothelial cells (ECs). Ang II (10(-7) mol/l) significantly increased intracellular ROS levels in ECs as measured by dichlorofluorescein (DCF) fluorescence. AM inhibited Ang II-stimulated ROS generation in a dose-dependent manner and this effect was abolished by a superoxide radical scavenger, NAD(P)H oxidase inhibitor, and a protein kinase A (PKA) inhibitor, and mimicked by a cell-permeable cAMP analog. A real-time reverse transcription-polymerase chain reaction (RT-PCR) study showed that Ang II significantly upregulated a set of redox-sensitive genes (ICAM-1, VCAM-1, PAI-1, tissue factor, MCP-1, osteopontin), and these effects were blocked by an antioxidant, N-acetyl cysteine (NAC). AM similarly and dose-dependently inhibited the Ang II-induced upregulation of the entire set of these genes via a receptor-mediated and PKA-dependent pathway, and the degrees of inhibition were similar to those by NAC. In conclusion, the present study demonstrated that AM potently blocked the Ang II-stimulated intracellular ROS generation from NAD(P)H oxidase and the subsequent redox-sensitive gene expression via a cAMP-dependent mechanism in ECs, suggesting that AM has vasculoprotective effects against pro-oxidant stimuli.
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PMID:Adrenomedullin inhibits angiotensin II-induced oxidative stress and gene expression in rat endothelial cells. 1602 44

The protein kinase C (PKC) family regulates macrophage function involved in host defense against infection. In the case of Leishmania donovani infection, the impairment of PKC-mediated signaling is one of the crucial events for the establishment of parasite into the macrophages. Earlier reports established that C-C chemokines mediated protection against leishmaniasis via the generation of nitric oxide after 48 h. In this study, we investigated the role of MIP-1alpha and MCP-1 in the regulation of impaired PKC activity in the early hours (6 h) of infection. These chemokines restored Ca2+-dependent PKC activity and inhibited Ca2+-independent atypical PKC activity in L. donovani-infected macrophages under both in vivo and in vitro conditions. Pretreatment of macrophages with chemokines induced superoxide anion generation by activating NADPH oxidase components in infected cells. Chemokine administration in vitro induced the migration of infected macrophages and triggered the production of reactive oxygen species. In vivo treatment with chemokines significantly restricted the parasitic burden in livers as well as in spleens. Collectively, these results indicate a novel regulatory role of C-C chemokines in controlling the intracellular growth and multiplication of L. donovani, thereby demonstrating the antileishmanial properties of C-C chemokines in the disease process.
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PMID:Regulation of impaired protein kinase C signaling by chemokines in murine macrophages during visceral leishmaniasis. 1629 31

Endothelial dysfunction (ED) complicates hypertension and is a precursor of atherosclerosis. Reduced NO bioactivity, because of increased reduced NAD(P)H oxidase-derived reactive oxygen species (ROS), plays a critical role in ED. gp91phox, predominantly expressed in the endothelium and adventitia, is a subunit of NAD(P)H oxidase important for its activation in response to angiotensin (Ang) II. Human atherosclerotic plaques are heavy laden with gp91phox. We have shown that in Dahl salt-sensitive (DS) rats, a paradigm of low renin salt-sensitive (SS) hypertension in humans, Ang II receptor blockade normalizes ROS production and endothelium-dependent relaxation (EDR) without significantly affecting systolic blood pressure (SBP). To additionally elucidate the mechanisms involved in the functional association of Ang II in SS hypertension, we administered a cell-permeable inhibitor of the assembly of p47phox with gp91phox in NAD(P)H oxidase, gp91ds-tat (10 mg/kg body weight, 3 weeks by minipump), to DS rats fed a 4% salt diet. Control rats received either vehicle or an inactive scramb-tat peptide. Vehicle-treated DS developed hypertension (SBP 168+/-5 mm Hg), left ventricular hypertrophy (LVH), proteinuria, impaired EDR, and increased aortic ROS production (superoxide 115% and peroxynitrite 157%) and expression of the proatherogenic molecules LOX-1 (130%) and MCP-1 (166%). gp91ds-tat, but not scramb-tat, normalized ROS and EDR, as well as LOX-1 and MCP-1, despite nonsignificant effects on SBP (159+/-5 mm Hg; P>0.05), left ventricular hypertrophy, and proteinuria. Our findings support the notion that in SS hypertension, activation of NAD(P)H oxidase promotes ED and atherogenesis via decreased nitric oxide bioactivity and increased LOX-1 and MCP-1, independent of blood pressure.
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PMID:Reduced NAD(P)H oxidase in low renin hypertension: link among angiotensin II, atherogenesis, and blood pressure. 1634 66

The role of polymorphonuclear neutrophils (PMN) in mediating diabetic tissue damage to the periodontium was investigated in a novel model of chronic hyperglycemia, the Akita mouse. Induction of acute peritoneal inflammation in wild-type (WT) and Akita mice resulted in exaggerated IL-6 response in Akita mice (2.9-fold increase over WT values) and a markedly increased chemokine response (KC, 2.6-fold; MCP-1, 2.6-fold; and MIP-1alpha, 4.4-fold increase over WT values). Chemotaxis to both fMLP and WKYMVm was significantly reduced in isolated Akita PMN compared with WT PMN as measured in a Boyden chamber. Superoxide release in contrast was significantly increased in Akita PMN as measured with cytochrome c reduction. Bone marrow-derived Akita PMN showed partial translocation of p47phox to the cell membrane without external stimulation, suggesting premature assembly of the superoxide-producing NADPH oxidase in hyperglycemia. In vivo studies revealed that ligature-induced periodontal bone loss is significantly greater in Akita mice compared with WT. Moreover, intravital microscopy of gingival vessels showed that leukocyte rolling and attachment to the vascular endothelium is enhanced in periodontal vessels of Akita mice. These results indicate that chronic hyperglycemia predisposes to exaggerated inflammatory response and primes leukocytes for marginalization and superoxide production but not for transmigration. Thus, leukocyte defects in hyperglycemia may contribute to periodontal tissue damage by impairing the innate immune response to periodontal pathogens as well as by increasing free radical load in the gingival microvasculature.
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PMID:Chronic hyperglycemia predisposes to exaggerated inflammatory response and leukocyte dysfunction in Akita mice. 1708 43

Increased oxidative stress in vascular cells is implicated in the pathogenesis of atherosclerosis. Reactive oxygen species (ROS) induce vascular inflammation via the proinflammatory cytokine/NF-kappaB pathway. Several lines of evidence suggest that peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1alpha) is an important regulator of intracellular ROS levels. However, no studies have examined the effects of PGC-1alpha on this process. We investigated the effects of PGC-1alpha on inflammatory molecule expression and activity of the redox-sensitive transcription factor, NF-kappaB, in vascular cells. PGC-1alpha expressed in human aortic smooth (HASMCs) and endothelial cells (HAECs) is upregulated by AMP-activated protein kinase activators, including metformin, rosiglitazone and alpha-lipoic acid. Tumor necrosis factor-alpha (TNF-alpha), a major proinflammatory factor in the development of vascular inflammation, stimulates intracellular ROS production through an increase in both mitochondrial ROS and NAD(P)H oxidase activity. Adenovirus-mediated overexpression of the PGC-1alpha gene in HASMCs and HAECs leads to a significant reduction in intracellular and mitochondrial ROS production as well as NAD(P)H oxidase activity. Consequently, NF-kappaB activity and MCP-1 and VCAM-1 induced by TNF-alpha are suppressed. Our data support the possibility that agents stimulating PGC-1alpha expression in the vasculature aid in preventing the development of atherosclerosis.
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PMID:Effects of PGC-1alpha on TNF-alpha-induced MCP-1 and VCAM-1 expression and NF-kappaB activation in human aortic smooth muscle and endothelial cells. 1718 71

Significant reduction of renal mass triggers a chain of events that result in glomerular hypertension/hyperfiltration, proteinuria, glomerulosclerosis, tubulointerstitial injury, and end-stage renal disease. These events are mediated by a constellation of hemodynamic, oxidative, and inflammatory reactions that are, in part, driven by local AT1 receptor (AT1r) activation by angiotensin II (Ang II). Here we explored the effects of 5/6 nephrectomy with and without AT1r blockade (losartan for 8 weeks) on AT1r and AT2r and Ang II-positive cell count, pathways involved in oxidative stress and inflammation [NAD(P)H oxidase, nuclear factor kappaB (NFkappaB), 12-lipooxygenase, cyclooxygenase (COX)-1, COX-2, monocyte chemoattractant protein (MCP)-1, plasminogen activator inhibitor (PAI)-1, renal T cell, and macrophage infiltration] as well as renal function and structure. The untreated group exhibited hypertension, deterioration of renal function and structure, reduced or unchanged plasma renin activity, aldosterone concentration, marked up-regulations of AT1r (250%), Ang II-expressing cell count (>20-fold), NAD(P)H oxidase subunits (gp91(phox,) p22(phox), and P47(phox); 20-40%), COX-2 (250%), 12-lipooxygenase (100%), MCP-1 (400%), and PAI-1 (>20-fold), activation of NFkappaB, and interstitial infiltrations of T cells and macrophages in the remnant kidneys. AT1r blockade attenuated the biochemical and histological abnormalities, prevented hypertension, and decelerated deterioration of renal function and structure. Thus, the study demonstrated a link between up-regulation of Ang II/AT1r system and oxidative stress, inflammation, hypertension, and progression of renal disease in rats with renal mass reduction.
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PMID:Intra-renal angiotensin II/AT1 receptor, oxidative stress, inflammation, and progressive injury in renal mass reduction. 1763 6


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