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)

Stress stimuli can lead to remodeling of the actin cytoskeleton and subsequent alteration of cell adhesion and permeation as well as cell functions and cell fate. We investigated redox-dependent Rho GTPase-linked pathways controlling the actin cytoskeleton in the inner ear of the CBA mouse, by using aminoglycoside antibiotics as a noxious stimulus that causes loss of sensory cells via the formation of reactive oxygen species. Kanamycin treatment in vivo interfered with the formation of F-actin, disturbed the arrangement of beta-actin in the stereocilia of outer hair cells, and altered the intermittent adherens junction/tight junction complexes between outer hair cells and supporting cells. The drug treatment also activated Rac1 and promoted the formation of the complex of Rac1 and p67phox while decreasing the activity of RhoA and reducing the formation of the RhoA/p140mDia complex. In inner-ear-derived cell lines, expression of mutated Rac1 changed the structural arrangement of F-actin and diminished the immunoreactivity of p140mDia. These findings suggest that actin depolymerization induced by kanamycin is mediated by Rac1 activation, followed by the formation of superoxide by NADPH oxidase. These changes will ultimately contribute to aminoglycoside-induced loss of hair cells.
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PMID:Rac/Rho pathway regulates actin depolymerization induced by aminoglycoside antibiotics. 1652 Nov 28

Studies were performed to test the hypothesis that the angiotensin-converting enzyme (ACE)/epidermal growth factor receptor (EGFR)/extracellular signal-regulated kinases (ERK) pathway, nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase/lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) pathway, and Rho-kinase pathway contribute to the pathogenesis of aldosterone/salt-induced hypertensive rats. Wistar rats were given 1% NaCl to drink and treated with one of the following combinations for 6 weeks: vehicle; aldosterone (0.75 microg/h); aldosterone plus a mineralocorticoid receptor antagonist, spironolactone (20 mg/kg/day); aldosterone plus an ACE inhibitor, imidapril (1 mg/kg/day); aldosterone plus an NAD(P)H oxidase inhibitor, apocynin (0.5 mmol/l); and aldosterone plus an Rho-kinase inhibitor, Y-27632 (3 mg/kg/day). Upregulated expression of ACE and EGFR and p44/p42ERK phosphorylation were suppressed by spironolactone or imidapril. Upregulated NAD(P)H oxidase subunits and LOX-1 expression were inhibited by spironolactone or apocynin. Increased expression of RhoA and Rho-kinase and myosin light chain phosphorylation were decreased by spironolactone or Y-27632. Moreover, these drugs effectively inhibited the vascular lesion formation, as measured by the medial thickness and level of perivascular fibrosis, and suppressed the expression of transforming growth factor-beta1, type I and III collagen, and monocyte chemoattractant protein-1 mRNA. Spironolactone may be useful as a cardioprotective agent to prevent cardiovascular remodeling via the ACE/EGFR/ERK, NAD(P)H oxidase/LOX-1, and Rho-kinase pathways.
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PMID:Cardioprotective mechanisms of spironolactone associated with the angiotensin-converting enzyme/epidermal growth factor receptor/extracellular signal-regulated kinases, NAD(P)H oxidase/lectin-like oxidized low-density lipoprotein receptor-1, and Rho-kinase pathways in aldosterone/salt-induced hypertensive rats. 1655 82

Spontaneous tone in large arteries may contribute to the pathogenesis of hypertension. Reactive oxygen species and Ca2+ influx have been shown to stimulate the development of spontaneous tone in isolated aortic rings in several models of hypertensive rats. The aim of this study was to investigate the role of the RhoA/Rho-kinase signaling pathway in the development of spontaneous tone in angiotensin II-induced hypertension and to explore the underlying mechanisms of RhoA/Rho-kinase activation. Our results showed that spontaneous tone was greatly enhanced in endothelium-denuded aortic rings from angiotensin II-induced hypertensive rats compared with their normotensive counterparts (73+/-5 versus 7+/-3% of phenylephrine-induced maximal contraction, respectively). The Rho-kinase inhibitor (R)-(+)-trans-N-(4-pyridyl)-4-(1-aminoethyl)-cyclohexanecarboxamide (Y-27632) (0.1-10 microM) concentration dependently inhibited spontaneous tone in aortic rings from angiotensin II-treated rats. NADPH oxidase inhibitors diphenylene iodonium and apocynin also significantly reduced spontaneous tone. Chronic angiotensin II treatment markedly increased RhoA protein expression (57%) but had no effect on Rho guanine nucleotide exchange factor mRNA or Rho-kinase protein expression levels. In endothelium-denuded rings from normotensive rats, angiotensin II (100 nM) increased RhoA membrane translocation and phosphorylation of the myosin light chain phosphatase target subunit, which were both blocked by the NADPH oxidase inhibitor diphenylene iodonium (10 microM). In conclusion, these data suggest that chronic treatment with angiotensin II leads to up-regulation of the RhoA/Rho-kinase pathway, contributing to spontaneous tone development in rat aorta. Increased NADPH oxidase-dependent reactive oxygen species may be one of the mechanisms mediating the RhoA/Rho-kinase activation.
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PMID:Increased RhoA/Rho-kinase signaling mediates spontaneous tone in aorta from angiotensin II-induced hypertensive rats. 1656 56

Senescence is accompanied by oxidative stress and cardiac dysfunction, although the link between the two remains unclear. This study examined the role of antioxidant metallothionein on cardiomyocyte function, superoxide generation, the oxidative stress biomarker aconitase activity, cytochrome c release, and expression of oxidative stress-related proteins, such as the GTPase RhoA and NADPH oxidase protein p47phox in young (5-6 mo) and aged (26-28 mo) FVB wild-type (WT) and cardiac-specific metallothionein transgenic mice. Metallothionein mice showed a longer life span (by approximately 4 mo) than FVB mice evaluated by the Kaplan-Meier survival curve. Compared with young cardiomyocytes, aged myocytes displayed prolonged TR(90), reduced tolerance to high stimulus frequency, and slowed intracellular Ca2+ decay, all of which were nullified by metallothionein. Aging increased superoxide generation, active RhoA abundance, cytochrome c release, and p47phox expression and suppressed aconitase activity without affecting protein nitrotyrosine formation in the hearts. These aging-induced changes in oxidative stress and related protein biomarkers were attenuated by metallothionein. Aged metallothionein mouse myocytes were more resistant to the superoxide donor pyrogallol-induced superoxide generation and apoptosis. In addition, aging-associated prolongation in TR90 was blunted by the Rho kinase inhibitor Y-27632. Collectively, our data demonstrated that metallothionein may alleviate aging-induced cardiac contractile defects and oxidative stress, which may contribute to prolonged life span in metallothionein transgenic mice.
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PMID:Metallothionein prolongs survival and antagonizes senescence-associated cardiomyocyte diastolic dysfunction: role of oxidative stress. 2703 33

Cyclooxygenase 2 (COX-2) is induced by microbial products, proinflammatory cytokines, growth factors, and oncogenes. The Rho family includes RhoA, Rac1, Rac2, Rac3, and Cdc42 and is involved in regulation of the actin cytoskeleton organization, cell growth, vesicular cell trafficking, and transcriptional regulation. Rac2 binds to NADPH oxidase protein complex, and Rac2 null neutrophils are known to have poor phagocytic activity. We examined whether Rac2, the predominant small GTPase in hematopoietic cells, influences COX-2 expression in bone marrow-derived macrophages (BMDM). We showed that BMDM from Rac2(-/-) null mice have reduced COX-2 expression in response to treatment with endotoxin. Despite a compensatory increase in Rac1, BMDM from Rac2(-/-) null mice have less biologically active GTP-bound Rac in response to LPS stimulation. Signaling molecules (downstream of Rac2 and Toll-like receptor 4) such as p42/44, p38, and pAKT were also affected in BMDM from Rac2(-/-) null mouse macrophages. We also observed that BMDM from Rac2(-/-) null failed to degrade IkappaBalpha significantly and had less immunoreactive PU.1. We show that both NF-kappaB pathway and PU.1 are involved in normal macrophage function and play a role in macrophage COX-2 expression. In summary, these data indicate that Rac2 regulates COX-2 expression in BMDM.
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PMID:Regulation of cyclooxygenase-2 expression by small GTPase Rac2 in bone marrow macrophages. 1757 12

The RhoA/Rho kinase (ROCK) pathway is a new mechanism of remodeling and vasoconstriction. Few data are available regarding ROCK activation when angiotensin I-converting enzyme is high and blood pressure is normal. We hypothesized that ROCK is activated in the vascular wall in normotensive rats with genetically high angiotensin I-converting enzyme levels, and it causes increased vascular expression of genes promoting vascular remodeling and also oxidative stress. Aortic ROCK activation, mRNA and protein levels (of monocyte chemoattractant protein-1, transforming growth factor [TGF]-beta(1), and plasminogen activator inhibitor-1 [PAI-1]), NADPH oxidase activity, and O(2)(*-) production were measured in normotensive rats with genetically high (Brown Norway [BN]) and low (Lewis) angiotensin-I-converting enzyme levels and in BN rats treated with the ROCK antagonist fasudil (100 mg/kg per day) for 7 days. ROCK activation was 12-fold higher in BN versus Lewis rats (P<0.05) and was reduced with fasudil by 100% (P<0.05). Aortic TGF-beta1, PAI-1, and monocyte chemoattractant protein-1 mRNA levels were higher in BN versus Lewis rats by 300%, 180%, and 1000%, respectively (P<0.05). Aortic TGF-beta1, PAI-1, and monocyte chemoattractant protein-1 protein levels were higher in BN versus Lewis rats (P<0,05). Fasudil reduced TGF-beta1 and PAI-1 mRNA and TGF-beta1, PAI-1, and monocyte chemoattractant protein-1 protein aortic levels to those observed in Lewis rats. Aortic reduced nicotinamide-adenine dinucleotide phosphate oxidase activity and (*)O(2)(-) production were increased by 88% and 300%, respectively, in BN rats (P<0.05) and normalized by fasudil. In conclusion, ROCK is significantly activated in the aortic wall in normotensive rats with genetically high angiotensin-I-converting enzyme and angiotensin II, and it causes activation of genes that promote vascular remodeling and also increases vascular oxidative stress.
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PMID:Rho kinase activation and gene expression related to vascular remodeling in normotensive rats with high angiotensin I converting enzyme levels. 1778 32

Alpha(2)-adrenoceptors potentiate renal vascular responses to angiotensin II via coincident signaling at phospholipase C. This leads to increased activation of the phospholipase C/protein kinase C/c-src pathway. Studies suggest that c-src activates the reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase/superoxide system, and reactive oxygen species stimulate the RhoA/Rho kinase pathway. Therefore, we hypothesized that NADPH oxidase/superoxide and RhoA/Rho kinase are downstream components of the signal transduction pathway that mediate the interaction between alpha(2)-adrenoceptors and angiotensin II on renal vascular resistance. In rat kidneys, both in vivo and in vitro, intrarenal infusions of angiotensin II increased renal vascular resistance, and UK14,304 (alpha(2)-adrenoceptor agonist) enhanced this response. Intrarenal Tempol (superoxide dismutase mimetic) or Y27632 (Rho kinase inhibitor) abolished the interaction between UK14,304 and angiotensin II both in vivo and in vitro. The interaction was also blocked by inhibitors of NADPH oxidase (in vivo using chronic gp91ds-tat administration and in vitro with diphenyleneiodonium). In cultured preglomerular vascular smooth muscle cells, UK14,304 enhanced angiotensin II-induced intracellular superoxide (2-hydroxyethidium production) and potentiated activation of RhoA (Western blot of activated RhoA bound to the binding domain of rhotekin). The interaction between angiotensin II and UK14,304 on superoxide generation and RhoA activation was blocked by inhibitors of phospholipase C (U73312), protein kinase C (GF109203X), c-src (PP1), NADPH oxidase (diphenyleneiodonium), or superoxide (Tempol). We conclude that NADPH oxidase/superoxide and RhoA/Rho kinase are involved in the interaction between alpha(2)-adrenoceptors and angiotensin II on renal vascular resistance by mediating signaling events downstream of the phospholipase C/protein kinase C/c-src pathway.
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PMID:Alpha2-adrenoceptors enhance angiotensin II-induced renal vasoconstriction: role for NADPH oxidase and RhoA. 1825 Mar 67

The statins, hydroxy-3-methylglutaryl-CoA reductase inhibitors that lower serum cholesterol, exhibit myriad clinical benefits, including enhanced vascular integrity. One potential mechanism underlying increased endothelial cell (EC) barrier function is inhibition of geranylgeranylation, a covalent modification enabling translocation of the small GTPases Rho and Rac to the cell membrane. While RhoA inhibition attenuates actin stress fiber formation and promotes EC barrier function, Rac1 inhibition at the cell membrane potentially prevents activation of NADPH oxidase and subsequent generation of superoxides known to induce barrier disruption. We examined the relative regulatory effects of simvastatin on RhoA, Rac1, and NADPH oxidase activities in the context of human pulmonary artery EC barrier protection. Confluent EC treated with simvastatin demonstrated significantly decreased thrombin-induced FITC-dextran permeability, a reflection of vascular integrity, which was linked temporally to simvastatin-mediated actin cytoskeletal rearrangement. Compared with Rho inhibition alone (Y-27632), simvastatin afforded additional protection against thrombin-mediated barrier dysfunction and attenuated LPS-induced EC permeability and superoxide generation. Statin-mediated inhibition of both Rac translocation to the cell membrane and superoxide production were attenuated by geranylgeranyl pyrophosphate (GGPP), indicating that these effects are due to geranylgeranylation inhibition. Finally, thrombin-induced EC permeability was modestly attenuated by reduced Rac1 expression (small interfering RNA), whereas these effects were made more pronounced by simvastatin pretreatment. Together, these data suggest EC barrier protection by simvastatin is due to dual inhibitory effects on RhoA and Rac1 as well as the attenuation of superoxide generation by EC NADPH oxidase and contribute to the molecular mechanistic understanding of the modulation of EC barrier properties by simvastatin.
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PMID:Endothelial cell barrier protection by simvastatin: GTPase regulation and NADPH oxidase inhibition. 1865 77

In the past decade understanding of the role of the Rho GTPases RhoA, Rac1 and Cdc42 has been developed from regulatory proteins that regulate specific actin cytoskeletal structures - stress fibers, lamellipodia and filopodia - to complex integrators of cytoskeletal structures that can exert multiple functions depending on the cellular context. Fundamental to these functions are three-dimensional complexes between the individual Rho GTPases, their specific activators (GEFs) and inhibitors (GDIs and GAPs), which greatly outnumber the Rho GTPases themselves, and additional regulatory proteins. By this complexity of regulation different vasoactive mediators can induce various cytoskeletal structures that enable the endothelial cell (EC) to respond adequately. In this review we have focused on this complexity and the consequences of Rho GTPase regulation for endothelial barrier function. The permeability inducers thrombin and VEGF are presented as examples of G-protein coupled receptor- and tyrosine kinase receptor-mediated Rho GTPase activation, respectively. These mediators induce complex but markedly different networks of activators, inhibitors and effectors of Rho GTPases, which alter the endothelial barrier function. An interesting feature in this regulation is that Rho GTPases often have both barrier-protecting and barrier-disturbing functions. While Rac1 enforces the endothelial junctions, it becomes part of a barrier-disturbing mechanism as activator of reactive oxygen species generating NADPH oxidase. Similarly RhoA is protective under basal conditions, but becomes involved in barrier dysfunction after activation of ECs by thrombin. The challenge and promise lies in unfolding this complex regulation, as this will provide leads for new therapeutic opportunities.
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PMID:Driving Rho GTPase activity in endothelial cells regulates barrier integrity. 2006 30

Hypertensive vasomotor dysfunction is defined by endothelium-dependent contractions involving prostaglandins and ROS. Since both thromboxane-prostanoid receptor (TPr) signaling and ROS activate RhoA-Rho kinase (ROCK) in vascular smooth muscle (VSM) preparations, we hypothesized that enhanced endothelium-dependent contraction in the common carotid artery (CCA) of spontaneously hypertensive rats (SHRs) is ROCK mediated. ACh-stimulated contractions were approximately twofold greater in SHRs versus normotensive Wistar-Kyoto (WKY) rats, abolished by endothelial denudation or cyclooxygenase (COX)-1 inhibition, and nearly eliminated by TPr blockade. RhoA but not ROCK-II protein expression was increased ( approximately 50%) in the SHR CCA. Inhibition of ROCK, but not protein kinase C, caused a dose-dependent reduction in endothelium-dependent contractions to ACh across strains, with the highest dose mirroring the effect of high-dose TPr antagonism. Conversely, ROCK inhibition caused dose-dependent and endothelium- and nitric oxide-independent relaxation in CCAs precontracted with the TPr agonist U-46619. Prostacyclin was the predominant prostaglandin produced by ACh-stimulated CCAs, with greater than twofold more prostacyclin released from SHR versus WKY rats, and its production was unaffected by ROCK inhibition. RhoA activation was approximately twofold higher in quiescent SHR CCAs compared with those from WKY rats and was significantly increased by ACh stimulation. Augmentation of chemical superoxide quenching with tiron or inhibition of the NADPH oxidase-derived superoxide-producing pathway with apocynin reduced ACh-stimulated contractile activity in SHR more than in WKY rats, whereas the SOD mimetic tempol amplified the response. Exposure of CCAs to exogenous H(2)O(2) caused contractions, similar to ACh stimulation, that were greater in SHR than in WKY rats, abolished by COX-1 inhibition, and highly attenuated by TPr blockade or ROCK inhibition. These results indicate that RhoA-ROCK may act as a molecular switch, transducing signals from endothelium-derived prostaglandin(s) and ROS, which are overproduced in SHR CCAs, to "turn on" VSM contractile pathways, thus mediating the enhanced endothelium- and endoperoxide-dependent vascular contractions characteristic of hypertension, among other cardiovascular disease states, such as diabetes and aging.
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PMID:RhoA-Rho kinase signaling mediates endothelium- and endoperoxide-dependent contractile activities characteristic of hypertensive vascular dysfunction. 2015 58


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