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

---

Query: EC:1.6.3.1 (NADPH oxidase)
11,281 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cardiovascular disease is prevalent in developed countries causing very large burdens to health services. The underlying pathology is atheromatous plaque in the sub-endothelial region of the vascular wall. High levels of low density lipoprotein cholesterol and high blood pressure cause endothelial damage. Atheroma develop from a response to this injury that is perpetuated to chronic inflammation. The invasion of inflammatory leukocytes into atheroma during its development and in the precipitation of acute thrombotic events is mediated by adhesion molecules on the cell surface. These are regulated by the actin filament cytoskeleton which also mediates intracellular signalling from them. The actin cytoskeleton is central to NADPH oxidase activation that produces superoxide which is an intracellular signalling molecule for the hypertensive and inflammatory actions of angiotensin II. There are polymorphisms in actin filament proteins such as adducin and caldesmon and in the promoter regions of tropomyosins that may cause individual variation in these processes. Many signalling molecules in the actin filament response to inflammatory stimuli and in signalling downstream from actin filaments are small G-proteins that require post-transcriptional modification by isoprenoids from the cholesterol synthetic pathway. Statins deplete the isoprenoids and so down regulate G-proteins that mediate the inflammatory response. Angiotensin converting enzyme inhibitors and angiotensin II receptor type 1 antagonists decrease angiotensin II stimulated superoxide production thus decreasing not only blood pressure but also inflammation. The anti-inflammatory effects of these drugs, involving altered actin filament function, are a major contributor to their benefits in the treatment of cardiovascular disease. The feasibility of modifying the behaviour of actin filament proteins as a therapeutic approach for cardiovascular disease is considered.
...
PMID:Inflammation in cardiovascular disease and regulation of the actin cytoskeleton in inflammatory cells: the actin cytoskeleton as a target. 1661 Oct 50

Activated matrix metalloproteinases (MMPs) in patients with acute coronary syndromes may contribute to plaque destabilization. Tumor necrosis factor-alpha (TNF-alpha) enhances NAD (P) H oxidase-dependent reactive oxygen species (ROS) formation and ROS induce MMP-2. In the present study, the effects of a potent water-soluble antioxidant, salvianolic acid B (SalB), derived from a Chinese herb, Salvia miltiorrhiza, on the expression of MMP-2 by TNF-alpha-treated human aortic smooth muscle cells (HASMCs) were investigated. In this study, salvianolic acid B scavenged H2O2 in a dose-dependent manner in test tube. We found that SalB, as well as NADPH oxidase inhibitors, DPI or apocynin, and antioxidant NAC, inhibited TNF-alpha-induced MMP-2 mRNA, protein expression, and gelatinolytic activity in HASMCs in a concentration-dependent manner. We also observed a dose-dependent decrease in ROS production and NADPH oxidase activity induced by TNF-alpha in the presence of SalB. SalB also significantly inhibited angiotensin II or H2O2-induced MMP-2 mRNA and protein expression and gelatinolytic activity in HASMCs. Our data point out that the importance of NADPH oxidase-dependent ROS generation in the control of SalB inhibition of TNF-alpha-induced MMP-2 expression and activity.
...
PMID:Salvianolic acid B from Salvia miltiorrhiza inhibits tumor necrosis factor-alpha (TNF-alpha)-induced MMP-2 upregulation in human aortic smooth muscle cells via suppression of NAD(P)H oxidase-derived reactive oxygen species. 1671 3

A high intake of the omega-3 fatty acid docosahexaenoate [docosahexaenoic acid (DHA)] has been associated with systemic antiinflammatory effects and cardiovascular protection. Cyclooxygenase (COX)-2 is responsible for the overproduction of prostaglandins (PG) at inflammatory sites, and its expression is increased in atheroma. We studied the effects of DHA on COX-2 expression and activity in human saphenous vein endothelial cells challenged with proinflammatory stimuli. A>or=24-h exposure to DHA reduced COX-2 expression and activity induced by IL-1, without affecting COX-1 expression. DHA effect depended on the NF-kappaB-binding site in the COX-2 promoter. EMSAs confirmed that DHA attenuated NF-kappaB activation. Because MAPK, PKC, and NAD(P)H oxidase all participate in IL-1-mediated COX-2 expression, we also tested whether these enzymes were involved in DHA effects. Western blots showed that DHA blocked nuclear p65 NF-kappaB subunit translocation by decreasing cytokine-stimulated reactive oxygen species and ERK1/2 activation by effects on both NAD(P)H oxidase and PKCepsilon activities. Finally, to address the question whether DHA itself or DHA-derived products were responsible for these effects, we inhibited the most important enzymes involved in polyunsaturated fatty acid metabolism, showing that 15-lipoxygenase-1 products mediate part of DHA effects. These studies provide a mechanistic basis for antiinflammatory and possibly plaque-stabilizing effects of DHA.
...
PMID:The omega-3 fatty acid docosahexaenoate attenuates endothelial cyclooxygenase-2 induction through both NADP(H) oxidase and PKC epsilon inhibition. 1701 45

Erectile dysfunction (ED) is a widespread condition, the incidence of which is increasing globally. ED is also indicative of underlying vasculopathy and represents a predictor of more serious cardiovascular disorders. Understanding the aetiology of ED may therefore provide invaluable pointers to the pathobiology of other cardiovascular diseases (CVDs) and syndromes. It follows, too, that therapeutic interventions that are successful in treating ED may, ipso facto, be effective in treating the early stages of conditions that include atherosclerosis, angina, plaque rupture and diabetic angiopathy. One common pathological denominator in both CVD and ED is oxidative stress, that is, the overproduction of reactive oxygen species (ROS), in particular, superoxide (O(2)(*-)) and hydrogen peroxide (H(2)O(2)). In this review, therefore, we consider the aetiology and pathobiology of O(2)(*-) in promoting ED and focus on NADPH oxidase as an inducible source of O(2)(*-) and H(2)O(2). Therapeutic strategies aimed at reducing oxidative stress to improve erectile function are also discussed.
...
PMID:Reactive oxygen species and erectile dysfunction: possible role of NADPH oxidase. 1705 77

Oxidative stress-mediated LDL modification has a key role in initiation of the atherosclerotic process. Platelets produce reactive oxidant species (ROS) upon stimulation with agonist, but it is uncertain whether they are able to oxidatively modify LDL. Human platelets taken from healthy subjects were incubated with LDL, then stimulated with collagen. Compared with unstimulated platelets, collagen-stimulated platelets induced LDL modification as shown by enhanced conjugated dienes and lysophosphatidylcholine formation, electrophoretic mobility, Apo B-100 degradation, and monocyte LDL uptake. Activated platelets also induced a marked reduction of vitamin E contained in LDL. A significant inhibition of LDL oxidation was observed in platelets treated with arachidonyl trifluomethyl ketone (AACOCF3), an inhibitor of phospholipase A2. The experiments reported above were also conducted in patients with hereditary deficiency of gp91phox, the central core of NADPH oxidase, and in patients with hypercholesterolemia. Platelets from gp91 phox-deficient patients produced a small amount of ROS and weakly modified LDL. Conversely, platelets from hypercholesterolemic patients showed enhanced ROS formation and oxidized LDL more than platelets from healthy subjects. This study provides evidence that platelets modify LDL via NADPH oxidase-mediated oxidative stress, a phenomenon that could be dependent on arachidonic acid activation. This finding suggests a role for platelets in favoring LDL accumulation within atherosclerotic plaque.
...
PMID:LDL are oxidatively modified by platelets via GP91(phox) and accumulate in human monocytes. 1719 95

Oxidative stress and inflammation processes are key components of atherosclerosis, from fatty streak formation to plaque rupture and thrombosis. Evidence has revealed that calcium-channel blockers (CCB) could retard atherogenesis, but the exact mechanisms have not been fully elucidated. The present study was undertaken to investigate the potential effects and molecular mechanisms of the CCB felodipine on the process of atherosclerosis in high-cholesterol-diet (HCD) apolipoprotein E-knockout (ApoE KO) mice. Adult male ApoE KO mice were given a normal diet (ND) or HCD and were randomized to no treatment or felodipine (5 mg / kg per day for 12 weeks). The ApoE KO mice with HCD were associated with a marked increase in plasma lipid levels, atherosclerotic lesion area, and the expressions of NADPH oxidase subunits (p47 and Rac-1), nuclear factor-kappaB (NF-kappaB) in nucleus, phosphor-inhibitors of kappaB (p-IkappaB), tumor necrosis-alpha (TNF-alpha), monocyte chemoattractant protein-1 (MCP-1), and vascular cell-adhesion molecule-1 (VCAM-1). These changes were suppressed in mice that were treated with felodipine (5 mg/kg per day for 12 weeks) concomitant with HCD administration, with no significant change in systolic blood pressure and plasma lipid levels. The results suggest that felodipine can attenuate atherosclerosis, and this effect is partly related to inhibition of oxidative stress and inflammatory signal-transduction pathways, which lead to decreases in the expression of inflammatory cytokines.
...
PMID:Molecular mechanisms of felodipine suppressing atherosclerosis in high-cholesterol-diet apolipoprotein E-knockout mice. 1828 87

Proliferation of vascular smooth muscle cells (VSMC), oxidative stress, and elevated inflammatory cytokines are some of the components that contribute to plaque formation in the vasculature. The cytokine tumor necrosis factor-alpha (TNF-alpha) is released during vascular injury, and contributes to lesion formation also by affecting VSMC proliferation. Recently, an A(2B) adenosine receptor (A(2B)AR) knockout mouse illustrated that this receptor is a tissue protector, in that it inhibits VSMC proliferation and attenuates the inflammatory response following injury, including the release of TNF-alpha. Here, we show a regulatory loop by which TNF-alpha upregulates the A(2B)AR in VSMC in vitro and in vivo. The effect of this cytokine is mimicked by its known downstream target, NAD(P)H oxidase 4 (Nox4). Nox4 upregulates the A(2B)AR, and Nox inhibitors dampen the effect of TNF-alpha. Hence, our study is the first to show that signaling associated with Nox4 is also able to upregulate the tissue protecting A(2B)AR.
...
PMID:TNF-alpha upregulates the A2B adenosine receptor gene: The role of NAD(P)H oxidase 4. 1864 98

Previous studies have shown a link between inhaled particulate matter (PM) exposure in urban areas and susceptibility to cardiovascular diseases. Although an oxidative stress pathway is strongly implicated, the locus of generation of reactive oxygen species (ROS) and the mechanisms by which these radicals exert their effects remain to be characterized. To test the hypothesis that exposure to environmentally relevant inhaled concentrated ambient PM (CAPs) enhances atherosclerosis through induction of vascular ROS and reactive nitrogen species. High-fat chow fed apolipoprotein E(-/-) mice were exposed to CAPs of less than 2.5 microm (PM(2.5)) or filtered air (FA), for 6 h/day, 5 days/week, for 4 months in Manhattan, NY. Atherosclerotic lesions were analyzed by histomorphometricly. Vascular reactivity, superoxide generation, mRNA expression of NADPH (nicotinamide adenine dinucleotide phosphate, reduced) oxidase subunits, inducible nitric oxide synthase, endothelial nitric oxide synthase, and GTP cyclohydrolase I were also assessed. Manhattan PM(2.5) CAPs were characterized by higher concentrations of organic and elemental carbon. Analysis of vascular responses revealed significantly decreased phenylephrine constriction in CAPs-exposed mice, which was restored by a soluble guanine cyclase inhibitor 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one. Vascular relaxation to A23187, but not to acetylcholine, was attenuated in CAPs mice. Aortic expression of NADPH oxidase subunits (p47(phox) and rac1) and iNOS were markedly increased, paralleled by increases in superoxide generation and extensive protein nitration in the aorta. The composite plaque area of thoracic aorta was significantly increased with pronounced macrophage infiltration and lipid deposition in the CAPs mice. CAPs exposure in Manhattan alters vasomotor tone and enhances atherosclerosis through NADPH oxidase dependent pathways.
...
PMID:Ambient particulates alter vascular function through induction of reactive oxygen and nitrogen species. 1918 7

Reactive oxidant species (ROS) seem to play a key role in the atherosclerotic process via a series of molecular changes that lead to macrophage infiltration in the endothelium and eventually to plaque formation. ROS are also implicated in arterial dysfunction via inactivation of nitric oxide, a potent vasodilator and antiaggregating molecule produced by the endothelium. Owing to the relevance of endothelial dysfunction and vascular inflammation in the process of human atherosclerosis, a lot of effort has been directed towards discovering the ROS-generating pathways implicated in the ROS upregulation. Amongst the enzymatic pathways, NADPH oxidase is the most important enzyme responsible for ROS formation in human vessels. Experimental and clinical studies suggested a role for this enzyme in initiation and progression of atherosclerotic disease. The purpose of this review is to analyze whether the basic and clinical studies are consistent with this hypothesis and to point out if determination of NADPH oxidase is useful in the setting of the atherosclerosis to predict its progression and clinical complications.
...
PMID:Role of NADPH oxidase in atherosclerosis. 1937 Dec 6

The anti-inflammatory properties of transforming growth factor-beta(1) (TGF-beta(1)) account for its protection against atherosclerotic plaque rupture. This study investigates whether activation of the Nrf2 (nuclear factor erythroid 2 [NF-E2]-related factor 2) transcription pathway is involved in TGF-beta(1) mediated induction of the antioxidant enzyme heme oxygenase-1 (HO-1) in smooth muscle cells (SMC). Human aortic smooth muscle cells (HAoSMC) or wild-type and Nrf2-deficient mouse (MAoSMC) aortic SMC were treated with TGF-beta(1) (2.5-10 ng/ml, 0-24 hrs). We report the first evidence that TGF-beta(1) induces Nrf2 mediated HO-1 expression and antioxidant response element activity, which was paralleled by enhanced superoxide production and expression of the NAD(P)H oxidase subunit p22(phox). TGF-beta(1) failed to induce HO-1 expression in MAoSMC derived from Nrf2-deficient mice, and HO-1 induction by TGF-beta(1) in HAoSMC was attenuated by inhibition of extracellular signal regulated kinase or c-jun-N-terminal kinase but not p38 mitogen activated protein kinase. Inhibition of NAD(P)H oxidase or scavenging of superoxide diminished HO-1 induction in response to TGF-beta(1). The oxidative stress agents glucose oxidase (GOx) and diethylmaleate enhanced TGF-beta(1) generation and HO-1 expression in HAoSMC, while antagonism of TGF-beta(1) signalling by adenoviral Smad7 overexpression attenuated their induction of HO-1. Pre-treatment of HAoSMC with TGF-beta(1) reduced nuclear translocation of the pro-apoptotic mediator p53 elicited by GOx. Our findings demonstrate that Nrf2 is a new target of TGF-beta(1) signalling in the vasculature which may contribute to the atheroprotective properties attributed to this growth factor.
...
PMID:Transforming growth factor-beta1 elicits Nrf2-mediated antioxidant responses in aortic smooth muscle cells. 1967 92


<< Previous 1 2 3 4 5 6 7 8 Next >>

---