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)

Monocyte extravasation into the vessel wall has been shown to be a critical step in the development of atherosclerosis. Upon activation, monocytes produce a burst of superoxide anion due to activation of the NADPH oxidase enzyme complex. Monocyte-derived superoxide anion contributes to oxidant stress in inflammatory sites, is required for monocyte-mediated LDL oxidation, and alters basic cell functions such as adhesion and proliferation. We hypothesize that monocyte-derived superoxide anion production contributes to atherosclerotic lesion formation. In this brief review, we summarize our current understanding of the signal transduction pathways regulating NADPH oxidase activation and related superoxide anion production in activated human monocytes. Novel pathways are identified that may serve as future targets for therapeutic intervention in this pathogenic process. The contributions of superoxide anion and NADPH oxidase to atherogenesis are discussed. Future experiments are needed to clarify the exact role of NADPH oxidase-derived superoxide anion in atherogenesis, particularly that derived from monocytes.
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PMID:Regulation of superoxide anion production by NADPH oxidase in monocytes/macrophages: contributions to atherosclerosis. 1452 94

VCAM-1 (vascular cell adhesion molecule-1) plays an important role in the regulation of inflammation in atherosclerosis, asthma, inflammatory bowel disease and transplantation. VCAM-1 activates endothelial cell NADPH oxidase, and this oxidase activity is required for VCAM-1-dependent lymphocyte migration. We reported previously that a mouse microvascular endothelial cell line promotes lymphocyte migration that is dependent on VCAM-1, but not on other known adhesion molecules. Here we have investigated the signalling mechanisms underlying VCAM-1 function. Lymphocyte binding to VCAM-1 on the endothelial cell surface activated an endothelial cell calcium flux that could be inhibited with anti-alpha4-integrin and mimicked by anti-VCAM-1-coated beads. VCAM-1 stimulation of calcium responses could be blocked by an inhibitor of intracellular calcium mobilization, a calcium channel inhibitor or a calcium chelator, resulting in the inhibition of NADPH oxidase activity. Addition of ionomycin overcame the calcium channel blocker suppression of VCAM-1-stimulated NADPH oxidase activity, but could not reverse the inhibitory effect imposed by intracellular calcium blockage, indicating that both intracellular and extracellular calcium mobilization are required for VCAM-1-mediated activation of NADPH oxidase. Furthermore, VCAM-1 specifically activated the Rho-family GTPase Rac1, and VCAM-1 activation of NADPH oxidase was blocked by a dominant negative Rac1. Thus VCAM-1 stimulates the mobilization of intracellular and extracellular calcium and Rac1 activity that are required for the activation of NADPH oxidase.
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PMID:Calcium mobilization and Rac1 activation are required for VCAM-1 (vascular cell adhesion molecule-1) stimulation of NADPH oxidase activity. 1459 51

Vascular NAD(P)H oxidase-derived reactive oxygen species (ROS) such as hydrogen peroxide (H2O2) have emerged as important molecules in the pathogenesis of atherosclerosis, hypertension, and diabetic vascular complications. Additionally, myeloperoxidase (MPO), a transcytosable heme protein that is derived from leukocytes, is also believed to play important roles in the above-mentioned inflammatory vascular diseases. Previous studies have shown that MPO-induced vascular injury responses are H2O2 dependent. It is well known that MPO can use leukocyte-derived H2O2; however, it is unknown whether the vascular-bound MPO can use vascular nonleukocyte oxidase-derived H2O2 to induce vascular injury. In the present study, ANG II was used to stimulate vascular NAD(P)H oxidases and increase their H2O2 production in the vascular wall, and vascular dysfunction was used as the vascular injury parameter. We demonstrated that vascular-bound MPO has sustained activity in the vasculature. MPO could use the vascular NAD(P)H oxidase-derived H2O2 to produce hypochlorus acid (HOCl) and its chlorinating species. More importantly, MPO derived HOCl and chlorinating species amplified the H2O2-induced vascular injury by additional impairment of endothelium-dependent relaxation. HOCl-modified low-density lipoprotein protein (LDL), a specific biomarker for the MPO-HOCl-chlorinating species pathway, was expressed in LDL and MPO-bound vessels with vascular NAD(P)H oxidase-derived H2O2. MPO-vascular NAD(P)H oxidase-HOCl-chlorinating species may represent a common pathogenic pathway in vascular diseases and a new mechanism involved in exacerbation of vascular diseases under inflammatory conditions.
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PMID:Interaction of myeloperoxidase with vascular NAD(P)H oxidase-derived reactive oxygen species in vasculature: implications for vascular diseases. 1461 14

Clinical and experimental evidence suggests that the pathways by which hypertension and dyslipidemia lead to vascular disease may overlap and that angiotensin II (Ang II) is involved in restructuring of the arterial wall in both atherosclerosis and hypertension. Ang II represents a potent proinflammatory agent promoting recruitment of monocytes into the vascular intima. Ang II also indirectly facilitates transformation of macrophages and smooth muscle cells into foam cells by promoting superoxide radical formation (via NADP/NADPH oxidase stimulation). The oxidative stress produced by Ang II leads to enhanced low-density lipoprotein oxidation and degradation of nitric oxide, an important vascular protective molecule capable of retarding atherosclerosis progression. The importance of the renin-angiotensin system (RAS) in atherogenesis is highlighted by studies in animal models as well as human beings indicating that inhibition of angiotensin-converting enzyme or blockade of type 1 Ang II receptors retards the development of atherosclerotic lesions. In light of a causal and central role of Ang II in atherogenesis, blockade of the RAS represents an important therapeutic consideration in the prevention and treatment of atherosclerotic disease.
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PMID:Renin-angiotensin system as a therapeutic target in managing atherosclerosis. 1470 95

A substantial proportion of individuals with coronary artery disease (CAD) has concomitant hypercholesterolemia. A large-scale association study was performed to identify separately genes that confer susceptibility to CAD in the absence or presence of nonfamilial hypercholesterolemia. The study population comprised 5248 unrelated Japanese individuals, including 3085 subjects with CAD (2350 men, 735 women) and 2163 controls (1329 men, 834 women). Among all study subjects, 2541 individuals (1688 men, 853 women) had nonfamilial hypercholesterolemia, and 2707 individuals (1991 men, 716 women) did not have this condition. The genotypes for 33 polymorphisms of 27 candidate genes were determined with a fluorescence- or colorimetry-based allele-specific DNA primer-probe assay system. Multivariate logistic regression analysis with adjustment for age, body mass index, and the prevalence of smoking, hypertension, diabetes mellitus, and hyperuricemia revealed that three polymorphisms [994G --> T (Val279Phe) in the platelet-activating factor acetylhydrolase gene, 242C --> T (His72Tyr) in the NADH/NADPH oxidase p22 phox gene, and 1100C --> T in the apolipoprotein C-III gene] were significantly associated with CAD in men with hypercholesterolemia. Genotyping of these three polymorphisms may prove informative for prediction of the genetic risk for CAD in men with nonfamilial hypercholesterolemia.
Atherosclerosis 2004 Jan
PMID:Association of gene polymorphisms with coronary artery disease in individuals with or without nonfamilial hypercholesterolemia. 1470 72

A multitude of studies in experimental animals, together with clinical data, provide evidence that increased production of ROS (reactive oxygen species) are involved in the development and progression of cardiovascular disease. As ROS appear to have a critical role in atherosclerosis, there has been considerable interest in identifying the enzyme systems involved and in developing strategies to reduce oxidative stress. Prospective clinical trials with vitamins and hormone replacement therapy have not fulfilled earlier promises, although there is still interest in other dietary supplements. Superoxide dismutase mimetics, thiols, xanthine oxidase and NAD(P)H oxidase inhibitors are currently receiving much interest, while animal studies using gene therapy show promise, but are still at an early stage. Of the drugs in common clinical use, there is evidence that ACE (angiotensin-converting enzyme) inhibitors and AT1 (angiotensin II type 1) receptor blockers have beneficial effects on oxidative stress above their antihypertensive properties, whereas statins, in addition to improving lipid profiles, may also lower oxidative stress.
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PMID:Strategies to reduce oxidative stress in cardiovascular disease. 1473 10

Thrombin has been implicated in the development of atherosclerosis and restenosis, in which migration of vascular smooth muscle cells (VSMC) is a crucial event. Thrombin-stimulated VSMC migration is associated with increased generation of reactive oxygen species (ROS), activation of mitogen-activated protein kinases (MAPKs), and production of growth factors and chemoattractants. In this study, we examined the interrelation of these signals to determine the pathway controlling thrombin-directed migration of human VSMC. Our results show that thrombin stimulated the production of ROS and activation of p38 MAPK. ROS were required for thrombin-induced VSMC migration since both generation of ROS and cell migration were significantly attenuated by inhibitors of NAD(P)H oxidase, diphenyleneiodonium (DPI) and apocynin (Apo.), and by the hydrogen peroxide scavenger, catalase (Cat.). Activation of p38 MAPK by thrombin was inhibited by DPI, Apo. and Cat., indicating ROS are used as messengers for activating this kinase. p38 MAPK is an important step since SB 203580, a selective inhibitor of p38 MAPK, suppressed the cell migration induced by thrombin. Furthermore, thrombin increased the expression of vascular endothelial growth factor (VEGF), a chemoattractant for VSMC, and this expression was inhibited by DPI, Apo., Cat. and SB 203580. Addition of anti-VEGF antibody significantly attenuated thrombin-induced migration. Collectively, the data presented here show that thrombin has stimulated VSMC migration and VEGF expression through an ROS-sensitive p38 MAPK pathway. VEGF synthesized and released by the cell served as a secondary mediator in thrombin-directed migration.
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PMID:Reactive oxygen species-sensitive p38 MAPK controls thrombin-induced migration of vascular smooth muscle cells. 1473 41

Hypertension is a risk factor for cardiovascular and cerebrovascular outcome. Hypertension is associated with oxidative stress. Alteration in endothelial function is an initial step in the pathogenesis of atherosclerosis. A balance between ambient levels of super oxide and released nitric oxide(NO) plays an important role in the maintenance of endothelial function. It is well known that reactive oxygen species, including hydroxy radicals, directly scavenge NO and produce toxic peroxynitrite. Angiotensin II and mechanical stress generate the reactive oxygen species through the activation of NADH/NADPH oxidase in hypertension. Several investigators have shown that oxidative stress is involved in enhanced vascular growth, vascular inflammation, and impaired endothelium-dependent in hypertension. In this review, we would like to explain the role of oxidative stress in hypertensive organ damages.
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PMID:[Oxidative stress, reactive oxygen species]. 1473 35

Reactive oxygen species (ROS) including nitric oxide (NO) and superoxide anion (O(2)(-)) are associated with cell migration, proliferation and many growth-related diseases. The objective of this study was to determine whether there was a reciprocal relationship between rat coronary microvascular endothelial cell (CMEC) growth and activity/expressions (mRNA and protein) of endothelial NO synthase (eNOS) and NAD(P)H oxidase enzymes. Proliferating namely, 50% confluent CMEC possessed approximately threefold increased activity and expression of both enzymes compared to 100% confluent cells. Treatment of CMEC with an inhibitor of eNOS (L-NAME, 100 microM) increased cell proliferation as assessed via three independent methods, i.e. cell counting, determination of total cellular protein levels and [(3)H]-thymidine incorporation. Similarly, treatment of CMEC with pyrogallol (0.3-3 mM), a superoxide anion (O(2)(-)) generator, also increased CMEC growth while spermine NONOate (SpNO), a NO donor, significantly reduced cell growth. Co-incubation of CMEC with a cell permeable superoxide dismutase mimetic (Mn-III-tetrakis-4-benzoic acid-porphyrin; MnTBAP) plus either pyrogallol or NO did not alter cell number and DNA synthesis thereby dismissing the involvement of peroxynitrite (OONO(-)) in CMEC proliferation. Specific inhibitors of NAD(P)H oxidase but not other ROS-generating enzymes including cyclooxygenase and xanthine oxidase, attenuated cell growth. Transfection of CMEC with antisense p22-phox cDNA, a membrane-bound component of NAD(P)H oxidase, resulted in substantial reduction in [(3)H]-thymidine incorporation, total cellular protein levels and expression of p22-phox protein. These data demonstrate a cross-talk between CMEC growth and eNOS and NAD(P)H oxidase enzyme activity and expression, thus suggesting that the regulation of these enzymes may be critical in preventing the initiation and/or progression of coronary atherosclerosis.
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PMID:Nitric oxide synthase and NAD(P)H oxidase modulate coronary endothelial cell growth. 1487 55

Accumulating evidence indicates that vascular dysfunction in atherosclerosis, hypertension, and diabetes is either caused by or accompanied by oxidative stress in the vessel wall. In particular, the role of redox processes as mediators of vascular repair and contributors to post-angioplasty restenosis is increasingly evident. Yet the pathophysiology of such complex phenomena is still unclear. After vascular injury, activation of enzymes such as NADPH oxidase leads to a marked increase in superoxide generation, proportional to the degree of injury, which rapidly subsides. Such early superoxide production is significantly greater after stent deployment, as compared to balloon injury. Recent data suggest the persistence of low levels of oxidant stress during the vascular repair reaction in neointimal and medial layers. Despite the compensatory increase in expression of iNOS and nNOS, nitric oxide bioavailability is reduced because of increased reaction rates with superoxide, yielding as by-products reactive nitrogen/oxygen species that induce protein nitration. Concurrently, the activity of vascular superoxide dismutases exhibits a sustained decrease following injury. This decreased activity appears to be a key contributor to vasoconstrictive remodeling and a major determinant of the occurrence of nitrative/oxidative stress. Replenishment of superoxide dismutase (SOD), as well as treatment with vitamins C and E or the lipid-lowering drug probucol and its analogs, led to decrease in constrictive remodeling and improved vessel caliber. Better understanding of the redox pathophysiology of vascular repair should help clarify the pathogenesis of many other vascular conditions and may provide novel therapeutic strategies to prevent vascular lumen loss.
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PMID:Redox processes underlying the vascular repair reaction. 1496 Nov 89


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