Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.6.3.1 (NADPH oxidase)
 11,281 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Until recently elevated blood pressure was considered as a hemodynamic entity representing an increase in workload for the heart and the arterial tree. Control of hypertension meant hemodynamic unloading, through inhibition of vasoconstrictor pathways, principally renin-angiotensin system and sympathetic system. In recent years however a new pharmacological approach has evolved as a result of (i) the dissociation of endothelial dysfunction and vascular pathology from increased blood pressure; (ii) the recognition that endothelial dysfunction regards not only the vascular reactivity, but also promotes atherosclerosis and thrombosis; and (iii) an improved understanding of the complexity of local-tissue renin angiotensin system and of the vasodilatory and cytoprotective role of natriuretic peptides. This has led to a reconsideration of existing medicines in terms of specification on endothelial function, more rationalized application of drugs and search for new compounds targeting both vasodilatory and anti-proliferative pathways. Examples include beta1-adrenergic antagonists, such as Nebivolol and Carvedilol, and vasopeptidase inhibitors, such as Omapatrilat, that inhibit simultaneously the angiotensin converting enzyme and neutral endopeptidase. Furthermore the identification of genetic polymorphisms in the effectors involved in the pathophysiology of hypertension or in the response to anti-hypertensive drugs, such as the p22phox subunit of NADPH oxidase, alpha-adducin or adrenergic receptors, has promoted the prospective of both better understanding of hypertension and individualized strategies for its treatment.
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PMID:The shift in the "paradigm" of the pharmacology of hypertension. 1496 15

Accumulating evidence suggests that several polymorphisms in factors regulating blood coagulation, platelet function, and lipid metabolism are relevant for susceptibility to ischemic cerebrovascular diseases (CVD). The present study analyzed 15 genetic polymorphisms possibly associated with atherosclerosis and thrombosis in a case-control study involving a total of 200 genetically unrelated Japanese patients with ischemic CVD (mean age 58.3 +/- 7.6 y) and 281 age- and gender-matched control subjects (59.0 +/- 4.1 y). Control subjects were randomly selected from unrelated donors with no history of documented CVD or any type of cardiovascular disease with normal resting electrocardiograms. Among the factors genotyped, two factors, platelet glycoprotein (GP) Ib alpha (Thr145Met) and NADPH oxidase p22phox (His72Tyr), were significantly associated with CVD after adjustment for acquired risk factors including hypertension, diabetes mellitus, hyperlipidemia, and smoking. For those with age < 60 y, 10.6% of the CVD patients and 2.9% of the control subjects had both of the two risk genotypes (GPIb alpha 145Met and p22phox 72Tyr, p < 0.05). The mean onset-age of CVD was 58.6 +/- 7.7 y for those having no or only one risk genotype, while 53.3 +/- 5.5 y for those having both of the risk genotypes (p < 0.05). Thus, GPIb alpha 145Met and p22phox 72 Tyr are the genetic factors associated with the risk of ischemic CVD in the Japanese. Carrying both of the two mutations might be associated with developing CVD at a younger age.
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PMID:[Genetic risk factors for ischemic cerebrovascular disease--analysis on fifteen candidate prothrombotic gene polymorphisms in the Japanese population]. 1496 55

There is a growing body of evidence that dihydropyridine-based calcium antagonists (DHPs) improve endothelial function, thus slowing the development and progression of atherosclerosis. However the molecular mechanisms by which DHPs normalize endothelial dysfunction, an initial step in atherosclerosis, are not fully understood. Monocyte recruitment and firm adhesion to endothelial cells play a central role in the pathogenesis of atherosclerosis. In this study, we investigated whether nifedipine, one of the most popular DHPs, could inhibit tumor necrosis factor-alpha (TNF-alpha)-induced reactive oxygen species (ROS) generation and subsequent monocyte chemoattractant protein-1 (MCP-1) expression in human umbilical vein endothelial cells (HUVEC). TNF-alpha significantly increased intracellular ROS generation in HUVEC, which was completely blocked by nifedipine. Nifedipine completely inhibited TNF-alpha-induced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity in HUVEC. Furthermore, nifedipine was found to significantly inhibit upregulation of MCP-1 messenger RNA levels in TNF-alpha-exposed HUVEC. The results demonstrate that nifedipine could inhibit TNF-alpha-induced MCP-1 overexpression in HUVEC by suppressing NADPH oxidase-mediated ROS generation. Our present study suggests that nifedipine may play a protective role in the development and progression of atherosclerosis through its antioxidative properties.
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PMID:Nifedipine inhibits tumor necrosis factor-alpha-induced monocyte chemoattractant protein-1 overexpression by blocking NADPH oxidase-mediated reactive oxygen species generation. 1501 5

Hyperhomocysteinaemia has recently been recognized as a risk factor of cardiovascular disease. However, the action mechanisms of homocysteine (Hcy) are not well understood. Given that Hcy may be involved in the recruitment of monocytes and neutrophils to the vascular wall, we have investigated the role of Hcy in essential functions of human neutrophils. We show that Hcy increased superoxide anion (O2*-) release by neutrophils to the extracellular medium, and that this effect was inhibited by superoxide dismutase and diphenyleneiodonium (DPI), an inhibitor of NADPH oxidase activity. The enzyme from rat peritoneal macrophages displayed a similar response. These effects were accompanied by a time-dependent increased translocation of p47phox and p67phox subunits of NADPH oxidase to the plasma membrane. We also show that Hcy increased intracellular H2O2 production by neutrophils, that Hcy enhanced the activation and phosphorylation of mitogen-activated protein kinases (MAPKs), specifically p38-MAPK and ERK1/2, and that the migration of neutrophils was increased by Hcy. Present results are the first evidence that Hcy enhances the oxidative stress of neutrophils, and underscore the potential role of phagocytic cells in vascular wall injury through O2*- release in hyperhomocysteinaemia conditions.
Atherosclerosis 2004 Feb
PMID:Homocysteine enhances superoxide anion release and NADPH oxidase assembly by human neutrophils. Effects on MAPK activation and neutrophil migration. 1501 32

To investigate the mechanisms that contribute to the acceleration of atherosclerosis in diabetes, the role of NAD(P)H oxidase in the enhanced proliferative capacity of diabetic vascular smooth muscle cells (VSMC) was studied. VSMC from streptozotocin (STZ)-induced diabetic rat aorta had increased proliferative capacity and generated higher levels of superoxide in comparison with cells from control rats. Both the enhanced proliferation and superoxide generation in diabetic VSMC were significantly attenuated not only by tiron (1mM), a superoxide scavenger but also by diphenyleneiodonium (DPI; 10microM), an NAD(P)H oxidase inhibitor. Both the activity of NAD(P)H oxidase and p22phox expression were significantly increased in diabetic VSMC. Furthermore, inhibition of p22phox expression by transfection of antisense p22phox oligonucleotides into diabetic VSMC resulted in a decrease in superoxide generation, which was accompanied by a significant attenuation of cell proliferation. Based on these results, it is suggested that diabetes-associated increase in NAD(P)H oxidase activity via enhanced expression of p22phox contributes to augmented VSMC proliferation in diabetic rats.
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PMID:p22phox-derived superoxide mediates enhanced proliferative capacity of diabetic vascular smooth muscle cells. 1503 21

Overproduction of reactive oxygen species or increased oxidative stress is considered a major mechanism involved in the pathogenesis of endothelial dysfunction, the initiation and progression of atherosclerosis and its adverse events. Evidence supports the importance of nitric oxide derived from endothelial nitric oxide synthase as a vasoprotective substance, and of vascular NAD(P)H oxidase-derived reactive oxygen species as important signaling molecules in vascular cells. Recent studies show that dysfunction of endothelial nitric oxide synthase in atherosclerosis generates O(2)(-) rather than nitric oxide, and that upregulation of vascular NAD(P)H oxidase is closely associated with atherosclerotic progression and plaque instability.
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PMID:Oxidant stress and atherosclerosis. 1506 53

Interleukin-8 (IL-8), a member of CXC chemokine family, has been found to play an important role in the pathogenesis of atherosclerosis. Tumor necrosis factor-alpha (TNF-alpha) is involved in the development and progression of atherosclerosis as well. In this study, we investigated whether and how azelnidipine, a newly developed long-acting calcium antagonist, could inhibit TNF-alpha-induced IL-8 expression in human umbilical vein endothelial cells (HUVEC). TNF-alpha significantly increased intracellular reactive oxygen species (ROS) generation in HUVEC, which was completely blocked by azelnidipine or apocynin, an inhibitor of NADPH oxidase. Azelnidipine also completely prevented TNF-alpha-induced increase in NADPH oxidase activity in HUVEC. Further, azelnidipine was found to significantly inhibit activator protein-1 (AP-1) promoter activity and IL-8 expression in TNF-alpha-exposed HUVEC. An inhibitor of AP-1, curcumin, or an anti-oxidant, N-acetylcysteine, also inhibited the TNF-alpha-induced IL-8 expression in HUVEC. These results demonstrated that azelnidipine inhibited TNF-alpha-induced IL-8 expression in HUVEC by blocking NADPH oxidase-mediated ROS generation and subsequent AP-1 activation. Our present study suggests that azelnidipine may play a protective role in the development and progression of atherosclerosis through its anti-oxidative properties.
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PMID:Azelnidipine, a newly developed long-acting calcium antagonist, inhibits tumor necrosis factor-alpha-induced interleukin-8 expression in endothelial cells through its anti-oxidative properties. 1507 61

Oxidative stress contributes to the pathogenesis of atherosclerosis. p22phox-based NAD(P)H oxidases exist in the vessel wall, acting as important superoxide-generating systems in the vasculature. Some studies have identified reduced atherosclerosis in the presence of the C242T CYBA polymorphism, whereas others have not. Because vascular p22phox is identical to neutrophil p22phox, we studied the association between the C242T, A640G, and -930A/G CYBA polymorphisms and the quantity of superoxide produced from neutrophils isolated from healthy adults to determine if these polymorphisms had any functional impact on NADPH oxidase function. Neutrophils were isolated from 90 subjects by Percoll density gradient centrifugation. Genotypes were determined by polymerase chain reaction (PCR) and restriction mapping, as well as real-time PCR. The oxidative burst was stimulated with phorbol 12-myristate 13-acetate. Superoxide was quantified using the superoxide dismutase inhibitable oxidation of the spin probe hydroxylamine 1-hydroxy-3-carboxy-pyrrolidine, detected by electron paramagnetic resonance. Superoxide production was significantly affected by the C242T polymorphism, being 8.7+/-0.7, 7.9+/-0.6, and 5.9+/-1.2 micromol/L per minute per 10(6) neutrophils for the C242T CC, CT, and TT genotypes, respectively (P<0.05). In contrast, the A640G and the -930A/G polymorphisms did not alter the neutrophil respiratory burst. Phagocytic respiratory burst activity in homozygous individuals with the T allele of the C242T CYBA polymorphism is significantly lower than of wild-type carriers and heterozygous individuals. Because p22phox exists in both the neutrophil and vessel wall, vascular oxidative stress is likely diminished in individuals with this polymorphism.
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PMID:C242T CYBA polymorphism of the NADPH oxidase is associated with reduced respiratory burst in human neutrophils. 1507 63

Plain old balloon angioplasty (POBA) is a useful therapeutic strategy especially for angioplasty of small coronary arteries. An association study was performed to identify genes that confer susceptibility to restenosis after POBA. The study population comprised 730 individuals (424 men, 306 women) who underwent successful POBA in at least one major coronary artery and were examined angiographically 6 months after the procedure. A total of 469 subjects (273 men, 196 women) exhibited no restenosis after POBA for any of the coronary lesions, whereas 261 subjects (151 men, 110 women) manifested restenosis for all lesions. The genotypes for 40 polymorphisms of 34 genes were determined with a fluorescence- or colorimetry-based allele-specific DNA primer-probe assay. Multivariate logistic regression analysis with adjustment for age, body mass index, and the prevalence of smoking, hypertension, diabetes mellitus, hypercholesterolemia, and hyperuricemia revealed that two polymorphisms (242C --> T in the NADH/NADPH oxidase p22 phox (p22-PHOX) gene and 2136C --> T in the thrombomodulin (THBD) gene) in men and two polymorphisms (584G --> A in the paraoxonase 1 (PON1) gene and 2445G --> A in the fatty acid-binding protein 2 (FABP2) gene) in women were significantly associated with restenosis after POBA. A stepwise forward selection procedure revealed that the effects of these polymorphisms on restenosis were statistically independent of conventional risk factors for coronary artery disease. Genotyping of these polymorphisms may prove informative for assessment of genetic risk for restenosis after POBA.
Atherosclerosis 2004 May
PMID:Genetic risk for restenosis after coronary balloon angioplasty. 1513 68

Chlamydia pneumoniae, a respiratory pathogen implicated in the development and progress of atherosclerosis, is known to infect and survive in macrophages, despite macrophage producing reactive oxygen species (ROS). To gain insight into ROS generation in macrophages infected with C. pneumoniae and to explore factors accounting for their final levels and effect, we investigated the role of NADPH oxidase and cytochrome oxidase pathways in the production and modulation of ROS. We also determined the operational role of Ca2+ signaling in the process. Macrophages stimulated with C. pneumoniae exhibit early release of ROS via up-regulation of NADPH oxidase and cytochrome c oxidase activities. Increasing the dose of C. pneumoniae led to an increase in the expression of these enzymes gene production, which was accompanied by a significant up-regulation of their gene products, implying a probable activation of transcriptional and translational processes, respectively. The change in levels of free Ca2+, influx across plasma membrane and efflux from intracellular store into cytosol all exhibited a significant regulatory role on the ROS generation pathways in macrophages. The observed events were shown to be dependent on binding of C. pneumoniae to CD14 receptors of macrophages. The data reported here imply that macrophages infected with C. pneumoniae produce ROS through membrane-associated NADPH oxidase with oxidative phosphorylation levels depending on Ca2+ influx signals.
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PMID:Elicitation of reactive oxygen species in Chlamydia pneumoniae-stimulated macrophages: a Ca2+-dependent process involving simultaneous activation of NADPH oxidase and cytochrome oxidase genes. 1519 88


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