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)

It is apparent that vascular tissues can produce reactive oxygen species, including the superoxide anion, and that their increased production can contribute to altered control of vasomotor tone and atherosclerosis. The NADH/NADPH oxidase system, which includes a 22 kD subunit (p22 phox), is the major source of superoxide production in vascular tissues. The superoxide radical oxidizes LDL and oxidized LDL is shown to be a key component in atherogenesis. Superoxide anion inactivates the NO radical, an anti-atherogenic molecule. Lysophosphatidylcholine, which accumulates during oxidative modification of LDL, has multiple effects on vascular cells, including cell proliferation, migration, apoptosis, and gene expression. Lysophosphatidylcholine stimulates superoxide production in endothelial cells through the NADH/NADPH oxidase-dependent mechanism. To investigate the expression of p22 phox in normal and atherosclerotic coronary arteries, samples were obtained from autopsy and examined using immunohistochemistry. In normal vessels, weak positive staining of p22 phox was detectable only in the adventitial layer. In contrast, strong immunoreactivity for p22 phox was present in atherosclerotic lesions around lipid core and shoulder regions. P22 phox was localized in the macrophages, fibroblasts, endothelial cells, and some smooth muscle cells which was identified by immunofluorescence double staining. The genetic analysis of the p22 phox gene by restriction fragment length polymorphism (RFLP) for control subject and patients with coronary artery disease revealed that the prevalence of the TC + TT genotype of the C242T polymorphism of the p22 phox gene in control subjects was significantly more frequent than in coronary artery disease patients, indicating that the mutation of the p22 phox gene might reduce the susceptibility for coronary artery disease, which is independent of other coronary risk factors. These observations suggest that oxidative stress, mainly via the NADH/NADPH oxidase system in the vasculature, may play an important role in the pathogenesis of atherosclerosis.
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PMID:Role of the vascular NADH/NADPH oxidase system in atherosclerosis. 1086 44

Stimulation of alpha1-adrenoceptors induces proliferation of vascular smooth muscle cells (SMCs) and contributes to arterial remodeling. Although activation of NAD(P)H oxidase and generation of reactive oxygen species (ROS) are required, little is known about this pathway. In this study, we examined the hypothesis that epidermal growth factor receptor (EGFR) transactivation and extracellular regulated kinases (ERK) are involved in alpha1-adrenoceptor-mediated SMC growth. Phenylephrine increased protein synthesis in association with a rapid (< or =5 minutes) and sustained (> or =60 minutes) doubling of phosphorylation of EGFR and ERK1/2, but not p38 or JNK in the media of rat aorta maintained in organ culture. Antagonists of EGFR phosphotyrosine activity (AG-1478) and ERK phosphorylation (PD-98059, U-0126) abolished phenylephrine-induced protein synthesis, whereas antagonists of p38 or JNK phosphorylation had no specific effect. A competitive antagonist (P22) for heparin binding EGF-like growth factor (HB-EGF) blocked phenylephrine-induced protein synthesis, as did downregulation of pro-HB-EGF (CRM197). Phenylephrine-induced protein synthesis was inhibited by neutralizing antibody to HB-EGF and absent in HB-EGF-/- SMCs. Inhibitors of metalloproteinases (BiPS, KB-R7785) also blocked adrenergic growth. The neutralizing antibody against HB-EGF had no effect on the two-fold increase in ROS generation induced by phenylephrine (DCF fluorescence), suggesting that stimulation of NAD(P)H oxidase by alpha1-adrenoceptor occupation precedes HB-EGF release. Cell culture studies confirmed and extended these findings. These data suggest that alpha1-adrenoceptor-mediated SMC growth requires ROS-dependent shedding of HB-EGF, transactivation of EGFR, and activation of the MEK1/2-dependent MAP kinase pathway. This trophic pathway may link sympathetic activity to arterial wall growth in adaptive remodeling and hypertrophic disease.
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PMID:Transactivation of epidermal growth factor receptor mediates catecholamine-induced growth of vascular smooth muscle. 1548 16

Superoxide anion (O(2)(-*)) production was previously reported to be increased in celiac ganglia (CG) during DOCA-salt hypertension, possibly via activation of the reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase. This suggested a role for neuronal NADPH oxidase in autonomic neurovascular control. However, the expression and localization of NADPH oxidase in the peripheral neurons are not fully known. The purpose of this study was to examine the subcellular localization of NADPH oxidase in sympathetic and sensory ganglion neurons and perivascular nerve fibers. In rat CG, p22(phox) and neuropeptide Y (NPY) were colocalized in all neurons. P22(phox) was also localized to dorsal root ganglia (DRG) neurons that contain calcitonin gene related peptide (CGRP). In mesenteric arteries, p22(phox) and p47(phox) were colocalized with NPY or CGRP in perivascular nerve terminals. A similar pattern of nerve terminal staining of p22(phox) and p47(phox) was also found in cultured CG neurons and nerve growth factor (NGF)-differentiated PC12 cells. These data demonstrate a previously uncharacterized localization of NADPH oxidase in perivascular nerve fibers. The presence of a O(2)(-*)-generating enzyme in close vicinity to the sites of neurotransmitter handling in the nerve fibers suggests the possibility of novel redox-mediated mechanisms in peripheral neurovascular control.
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PMID:Localization of NADPH oxidase in sympathetic and sensory ganglion neurons and perivascular nerve fibers. 1971 51

Limb remote ischemic postconditioning (LRIP) can reduce ischemia-reperfusion injury (IRI), but its mechanisms are still unclear. We hypothesize that LRIP reduces IRI by reversing eNOS uncoupling. Focal ischemia was induced in Sprague-Dawley rats by middle cerebral artery occlusion for 2 h followed by a 24 h reperfusion. Before this surgery, folic acid (FA) was administered to the drug treatment group by gavage for 11 days. After a 24 h reperfusion, behavioural testing, vascular function, NO concentration and superoxide dismutase activity in the serum were determined. In addition, the infarct size of the brain was also detected. The mRNA of eNOS, nNOS, GTP cyclohydrolase I (GTPCH), P22(phox) and xanthine oxidase (XO) in the ischemic region were detected by RT-PCR, and nitrotyrosine (Tyr-NO2) was detected using Western blot analysis. The results showed that LRIP, FA and FA+LRIP all could improve behavioural score, and increase NO-mediated endothelium-dependent vasomotor responses, reduce infarction of rats subjected to IRI. Western blot and RT-PCR analyses showed that the Tyr-NO2 levels and the mRNA expression of NADPH oxidase catalytic subunit P22(phox) and XO were up-regulated in the ischemic brain, which was significantly inhibited by LRIP, FA and FA+LRIP. The mRNA expression of the rate-limiting enzyme in BH4 synthesis, GTPCH, was down-regulated in the ischemic brain, which could be significantly augmented by LRIP and FA+LRIP. It can be concluded that IRI induces eNOS uncoupling in the cerebral ischemic region and LRIP partially reverses the eNOS uncoupling induced by IRI.
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PMID:Limb remote ischemic post-conditioning reduces brain reperfusion injury by reversing eNOS uncoupling. 2495 90

Aging has been associated with oxidative stress and the accumulation of mitochondrial DNA (mtDNA) mutation. The previous study has established a mimetic rat model of aging using D-galactose (D-gal) and revealed that chronic injection of D-gal can increase NADPH oxidase (NOX)-dependent oxidative stress, mitochondrial damage and apoptosis in the peripheral auditory system. However, the effects of NOXs in the central auditory system (CAS) were still obscure. The current study was designed to investigate potential causative mechanisms of central presbycusis by using the D-gal-induced aging rats. We found that the levels of H2O2 and the expression of NADPH oxidase 2 (NOX2) and its corresponding subunits P22(phox), P47(phox) and P67(phox) were greatly increased in the ventral cochlear nucleus (VCN) of D-gal-treated rats as compared with controls. And, the levels of a typical biomarker of oxidative stress, 8-hydroxy-2-deoxyguanosine (8-OHdG), and the accumulation of mtDNA common deletion (CD) were also increased in the VCN of D-gal-treated rats as compared with controls. Moreover, the damage of mitochondrial ultrastructure, a decline in ATP levels, the loss of mitochondrial membrane potential (MMP), an increase in the amount of cytochrome c (cyt c) translocated to the cytoplasm and caspase-3 activation were observed in the VCN induced by D-gal. In addition, we also found that the terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) nick-end-labeling (TUNEL)-positive cells in the VCN were increased in D-gal-treated rats. Taken together, these findings suggest that NOX2-dependent oxidative stress may contribute to mitochondrial damage and activate a caspase-3-dependent apoptosis pathway in the CAS during aging. This study also provides new insights into the development of presbycusis.
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PMID:NADPH oxidase 2-dependent oxidative stress, mitochondrial damage and apoptosis in the ventral cochlear nucleus of D-galactose-induced aging rats. 2549 16