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)

1. The generation of superoxide anions (O2-) by intact pig coronary artery rings was measured using a lucigenin-enhanced chemiluminescence technique and a histochemical technique with Nitroblue Tetrazolium (NBT) staining. 2. Isolated arteries with intact endothelium generated O2- at a rate of 9.0 +/- 0.8 pmol min-1 (mg dry weight)-1; this rate was diminished by about 24% when the endothelium was removed. The NBT staining of arterial ring preparations showed formazan precipitation mainly in the intima. Arterial rings were pretreated with diethylthiocarbamate in order to inhibit Cu-Zn superoxide dismutase (SOD) activity which increased the O2- generation by 184 +/- 55% (n = 10; P < 0.01). Stimulation of protein kinase C with phorbol 12-myristate 13-acetate (5 microM) enhanced endothelium-dependent O2- generation by 136 +/- 20% (n = 19; P < 0.01). Neither stimulation with bradykinin or substance P, nor inhibition with NG-nitro-L-arginine methyl ester of endothelial nitric oxide synthase had a significant effect on O2- generation. In contrast, the inhibition of flavoproteins with diphenyliodonium decreased concentration-dependent O2- generation (IC50, 1.85 +/- 5.33 microM). Inhibition of tetrahydrobiopterin synthesis with 2,4-diamino-6-hydroxy-pyrimidine resulted in a reduced generation of O2- by about 55%. 3. The addition of 100 microM NADH and 100 microM NADPH resulted in an excessive generation of O2- at a rate of 0.68 +/- 0.03 and 0.26 +/- 0.01 nmol O2- min-1 (mg protein)-1, respectively, in the membrane fraction, but not in the cytosolic fraction, of homogenates obtained from arteries. 4. The results suggest that intact coronary arteries do generate O2- under basal conditions and that the endothelial layer significantly contributes to this phenomenon. This generation of O2- is greatly influenced by intrinsic SOD activity. It is suggested that basal vascular O2- generation is mainly due to membrane-bound NAD(P)H oxidase activity and/or tetrahydrobiopterin-dependent processes.
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PMID:Endothelial-derived superoxide anions in pig coronary arteries: evidence from lucigenin chemiluminescence and histochemical techniques. 914 21

Angiotensin II stimulates vascular NADPH oxidase to produce superoxide, which can react with nitric oxide and impair vasomotor function. We tested the hypothesis that the overexpression of endothelial nitric oxide synthase (eNOS) or superoxide dismutase (SOD) would correct angiotensin II-induced endothelial dysfunction. We examined the effects of the gene transfer of eNOS or 2 isoforms of SOD to the aorta in angiotensin II-treated rabbits on vasomotor function. New Zealand White rabbits were treated for 1 week with angiotensin II (100 ng. kg(-1). min(-1)) or saline by osmotic minipumps. In angiotensin II-treated rabbits, mean blood pressure was 107+/-8 mm Hg; it was 67+/-5 mm Hg in saline-infused rabbits (P<0.05). In aortas from angiotensin II-treated rabbits, lucigenin-enhanced chemiluminescence demonstrated a 2.5-fold increase in superoxide levels, and the oxidative fluorescent probe hydroethidine indicated increased superoxide levels throughout the vascular wall, especially in the endothelium and adventitia. Maximal relaxation to acetylcholine was less in aortas from rabbits treated with angiotensin II (72+/-5% versus 87+/-4% in saline-treated rabbits; P<0.01), but responses to sodium nitroprusside were similar. Segments of the thoracic aorta were incubated in vitro with an adenoviral vector that expressed eNOS, copper zinc SOD (CuZnSOD), extracellular SOD (ECSOD), or beta-galactosidase. beta-Gal treatment with adenovirus containing the gene for eNOS (AdeNOS) but not adenovirus containing the gene for beta-gal (Adbeta-gal) (control virus) restored responses to acetylcholine (82+/-3% after AdeNOS and 67+/-4% after Adbeta-gal). Gene transfer of CuZnSOD or ECSOD did not improve the endothelium-dependent relaxation of the aorta in rabbits that received angiotensin II. Thus, gene transfer of eNOS, but not SOD, effectively restores vasomotor function in angiotensin II-infused rabbits.
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PMID:Gene transfer of endothelial nitric oxide synthase reduces angiotensin II-induced endothelial dysfunction. 1067 3

The term oxidative stress refers to a situation in which cells are exposed to excessive levels of either molecular oxygen or chemical derivatives of oxygen (ie, reactive oxygen species). Three enzyme systems produce reactive oxygen species in the vascular wall: NADH/NADPH oxidase, xanthine oxidoreductase, and endothelial nitric oxide synthase. Among vascular reactive oxygen species superoxide anion plays a critical role in vascular biology because it is the source for many other reactive oxygen species and various vascular cell functions. It is currently thought that increases in oxidant stress, namely excessive production of superoxide anion, are involved in the pathophysiology of endothelial dysfunction that accompanies a number of cardiovascular risk factors including hypercholesterolemia, hypertension and cigarette smoking. On the other hand, vascular oxidant stress plays a pivotal role in the evolution of clinical conditions such as atherosclerosis, diabetes and heart failure.
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PMID:Vascular oxidant stress: molecular mechanisms and pathophysiological implications. 1087 82

Accumulating evidence suggests that oxidant stress alters many functions of the endothelium, including modulation of vasomotor tone. Inactivation of nitric oxide (NO(.)) by superoxide and other reactive oxygen species (ROS) seems to occur in conditions such as hypertension, hypercholesterolemia, diabetes, and cigarette smoking. Loss of NO(.) associated with these traditional risk factors may in part explain why they predispose to atherosclerosis. Among many enzymatic systems that are capable of producing ROS, xanthine oxidase, NADH/NADPH oxidase, and uncoupled endothelial nitric oxide synthase have been extensively studied in vascular cells. As the role of these various enzyme sources of ROS become clear, it will perhaps be possible to use more specific therapies to prevent their production and ultimately correct endothelial dysfunction.
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PMID:Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. 1107 78

The maintenance of balance between nitric oxide (NO) and the superoxide anion is required for proper functioning of the endothelium. To investigate the relationship between genetic factors associated with endothelial function and the development of coronary artery disease (CAD), endothelial nitric oxide synthase (ecNOS) gene a/b polymorphism and NADH/NADPH oxidase p22 phox gene C242T polymorphism were examined in 305 Korean male CAD patients and 215 healthy male control subjects. The beta-fibrinogen gene H1/H2 polymorphism was also analyzed. Both ecNOS a/b and p22 phox C242T polymorphisms were found to be associated with the development of CAD in the study population (p=0.020 and 0.011, respectively). When the association was analyzed by age, statistical significance was retained only in those <51 years (p=0.021 and 0.025 for the a/b and the C242T polymorphism, respectively) and not in those >51 years of age (p=0.155 and 0.278 respectively). However, the distribution of the beta-fibrinogen H1/H2 genotypes was not found to be associated with the development of CAD in either the < or =50 (p = 0.611) or >50 groups (p = 0.188). The ecNOS gene a/b polymorphism and the NADH/NADPH oxidase p22 phox gene C242T polymorphism were found to be significantly associated with the development of CAD in Korean male patients less than 51 years old.
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PMID:Genetic factors associated with endothelial dysfunction affect the early onset of coronary artery disease in Korean males. 1153 Sep 61

We investigated the hypothesis that the antiatherosclerotic effect of 17beta-estradiol (E2) is due to a shift in the nitric oxide (NO)/superoxide (O2-) balance in the vessel wall, thereby increasing the bioavailability of NO. In human umbilical vein cultured endothelial cells, E2 (1-100 nmol/l), but not 17alpha-estradiol, caused a time- and concentration-dependent decrease in expression of the NADPH oxidase subunit gp91phox (up to 60% inhibition at both the mRNA and protein level). This effect was prevented by coincubation with the estrogen receptor antagonists tamoxifen and ICI 182,780 (1 micromol/l each). Within the same concentration range, E2 also up-regulated endothelial nitric oxide synthase expression ( approximately twofold). Moreover, preincubation of the cells with E2 or a gp91phox antisense oligonucleotide significantly decreased their capacity to generate O2- on phorbol ester stimulation (i.e., assembly of the active NADPH oxidase complex). Blockade of NO synthase activity, on the other hand, had no effect on phorbol ester-stimulated O2- formation. In addition, E2 (100 nmol/l) inhibited the increase in adhesion molecule and chemokine expression in cells exposed to cyclic strain. Cyclic strain enhanced endothelial O2- formation, thereby offsetting the inhibitory effect of NO on the expression of these gene products. E2 thus seems to act as an antioxidant at the genomic level which by improving the NO/O2- balance normalizes expression of proatherosclerotic gene products in endothelial cells.
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PMID:17beta-estradiol inhibition of NADPH oxidase expression in human endothelial cells. 1164 Dec 38

Angiotensin II infusion causes endothelial dysfunction by increasing NAD(P)H oxidase-mediated vascular superoxide production. However, it remains to be elucidated how in vivo angiotensin II treatment may alter the expression of the gp91(phox) isoforms and the endothelial nitric oxide synthase (NOS III) and subsequent signaling events and whether, in addition to the NAD(P)H oxidase, NOS III contributes to vascular superoxide formation. We therefore studied the influence of in vivo angiotensin II treatment (7 days) in rats on endothelial function and on the expression of the NAD(P)H oxidase subunits p22(phox), nox1, nox4, and gp91(phox) and NOS III. Further analysis included the expression of NO-downstream targets, the soluble guanylyl cyclase (sGC), the cGMP-dependent protein kinase I (cGK-I), and the expression and phosphorylation of the vasodilator-stimulated phosphoprotein (VASP) at Ser239 (P-VASP). Angiotensin II caused endothelial dysfunction and increased vascular superoxide. Likewise, we found an increase in vascular protein kinase C (PKC) activity, in the expression of nox1 (6- to 7-fold), gp91(phox) (3-fold), p22(phox) (3-fold), NOS III mRNA, and protein. NOS-inhibition with N(G)-nitro-L-arginine decreased superoxide in vessels from angiotensin II-treated animals, compatible with NOS-uncoupling. Vascular NO assessed with electron paramagnetic resonance was markedly reduced. Likewise, a decrease in sGC-expression and P-VASP levels was found. In vivo PKC-inhibition with chelerythrine reduced angiotensin II-induced superoxide production and markedly inhibited upregulation of NAD(P)H oxidase subunits. We therefore conclude that angiotensin II-induced increases in the activity and the expression of NAD(P)H oxidase are at least in part PKC-dependent. NADPH oxidase-induced superoxide production may trigger NOS III uncoupling, leading to impaired NO/cGMP signaling and to endothelial dysfunction in this animal model. The full text of this article is available at http://www.circresaha.org.
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PMID:Effects of angiotensin II infusion on the expression and function of NAD(P)H oxidase and components of nitric oxide/cGMP signaling. 1188 82

1. The biosynthesis of endothelin-1 is increased in the diabetic state. So this peptide may cause diabetic vascular complications. We tested this possibility by chronically administering J-104132, a potent orally active mixed antagonist of endothelin A and B (ET(A)/ET(B)) receptors to streptozotocin (STZ)-induced diabetic rats and focusing on changes in endothelial function. 2. The acetylcholine (ACh)-induced endothelium-dependent relaxation was impaired in diabetic rats and this impairment was significantly attenuated following chronic administration of J-104132 (10 mg kg(-1), p.o., daily for 4 weeks). 3. In an in vitro experiment using aortae from diabetic rats, the ACh-induced relaxation was not changed by the presence of J-104132 (3 x 10(-9) M). 4. The expression levels of the mRNA for endothelial nitric oxide synthase was comparable among aortae from the three groups (control, diabetic and chronically J-104132-treated diabetic). 5. The amount of superoxide anion was significantly greater in aortae from diabetic rats than in controls. Chronic J-104132 treatment significantly decreased the level of superoxide anion in diabetic rats. 6. The expression of the p22phox mRNA for the NADH/NADPH oxidase subunit was significantly increased in STZ-induced diabetic rats and this increase was completely prevented by chronic administration of J-104132. 7. These results suggest that in STZ-induced diabetic rats, ET-1 may be directly involved in impairing endothelium-dependent relaxation via increased superoxide-anion production.
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PMID:Effects of chronic administration of the novel endothelin antagonist J-104132 on endothelial dysfunction in streptozotocin-induced diabetic rat. 1195 96

We have shown previously that ischemia in an isolated rat lung that is normally oxygenated by continued ventilation results in lipid and protein oxidation, indicating the generation of reactive oxygen species. By using a variety of biochemical and imaging techniques, we determined that the initial response, which occurs within the first second of ischemia, is partial depolarization of the endothelial cell plasma membrane. This event is followed within several seconds by activation of endothelial NADPH oxidase and generation of superoxide anion at the extracellular surface of the cell membrane where it is dismutated to freely diffusible H2O2. Approximately 15 secs after the onset of ischemia, we detected an elevation of intracellular Ca2+ caused by its release from intracellular stores, followed by Ca2+ influx, possibly through T-type voltage-dependent Ca2+ channels. Increased nitric oxide generation through activation of endothelial nitric oxide synthase is detected after about 45 secs of ischemia. These changes (endothelial membrane depolarization, reactive oxygen species production, elevation of intracellular Ca2+ levels, and nitric oxide generation) were confirmed in isolated endothelial cells that had been adapted to shear stress in vitro. The in vitro model also demonstrates reactive oxygen species-dependent activation of nuclear factor-kappaB and activator protein-1 and that 24 hrs of ischemia results in increased cell division. These results indicate a novel cell-signaling pathway in response to loss of shear stress. The basis for these changes in endothelial function is related to mechanotransduction, i.e., altered shear stress rather than a metabolic response to ischemia. The biological function for the response may be an attempt to restore blood flow through vasodilatation and new capillary formation.
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PMID:Shear stress and endothelial cell activation. 1200 35

Nonenzymatic glycosylation of plasma proteins may contribute to the excess risk of developing atherosclerosis in patients with diabetes mellitus. Although it is believed that high-density lipoprotein (HDL) is glycosylated at an increased level in diabetic individuals, little is known about a possible linkage between glycated HDL and endothelial dysfunction in diabetes. To clarify whether glucose-modified HDL affects the function of endothelial cells, we first examined herein the level of H(2)O(2) generation from cultured human aortic endothelial cells (HAECs) exposed to a glycated oxidized HDL (gly-ox-HDL) prepared in vitro. Incubation for 48 hours with 100 microg/mL of gly-ox-HDL induced significant release of H(2)O(2) from cells and gly-ox-HDL-induced H(2)O(2) formation was inhibited in the presence of diphenyleneiodonium, an inhibitor of NADPH oxidase. In addition, stimulation of HAECs with gly-ox-HDL for 48 hours elicited a marked downregulation of catalase and Cu(2+), Zn(2+)-superoxide dismutase (CuZn-SOD), suggesting H(2)O(2) formation by gly-ox-HDL to be due to a disturbance involving oxidant and antioxidant enzymes in the cells. Treatment of HAECs with gly-ox-HDL attenuated the expression of endothelial nitric oxide synthase (eNOS), but not inducible nitric oxide synthase (iNOS), and this was followed by decreased production of nitric oxide (NO) by the cells. Furthermore, in vitro experiments with glycated HDL (gly-HDL) in the presence of 2 mmol/L EDTA and Cu(2+)-oxidized HDL suggested the effect of gly-HDL on endothelial function to be possibly potentiated by additional oxidative modification. Taking all of the above findings together, gly-ox-HDL may lead to the deterioration of vascular function through altered production of reactive oxygen species and reactive nitrogen species in endothelial cells.
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PMID:Glycated high-density lipoprotein regulates reactive oxygen species and reactive nitrogen species in endothelial cells. 1252 61


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