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)

In many types of cardiovascular pathophysiology such as hypercholesterolemia and atherosclerosis, diabetes, cigarette smoking, or hypertension (with its sequelae stroke and heart failure) the expression of endothelial NO synthase (eNOS) is altered. Both up- and downregulation of eNOS have been observed, depending on the underlying disease. When eNOS is upregulated, the upregulation is often futile and goes along with a reduction in bioactive NO. This is due to an increased production of superoxide generated by NAD(P)H oxidase and by an uncoupled eNOS. A number of drugs with favorable effects on cardiovascular disease upregulate eNOS expression. The resulting increase in vascular NO production may contribute to their beneficial effects. These compounds include statins, angiotensin-converting enzyme inhibitors, AT1 receptor antagonists, calcium channel blockers, and some antioxidants. Other drugs such as glucocorticoids, whose administration is associated with cardiovascular side effects, downregulate eNOS expression. Stills others such as the immunosuppressants cyclosporine A and FK506/tacrolimus or erythropoietin have inconsistent effects on eNOS. Thus regulation of eNOS expression and activity contributes to the overall action of several classes of drugs, and the development of compounds that specifically upregulate this protective enzyme appears as a desirable target for drug development.
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PMID:Regulation of endothelial-type NO synthase expression in pathophysiology and in response to drugs. 1238 13

Intravital microscopic techniques were used to examine the mechanisms underlying bradykinin-induced leukocyte/endothelial cell adhesive interactions (LECA) and venular protein leakage (VPL) in single postcapillary venules of the rat mesentery. The effects of bradykinin superfusion to increase LECA and VPL were prevented by coincident topical application of either a bradykinin-B(2) receptor antagonist, a cell-permeant superoxide dismutase (SOD) mimetic or antioxidant, or inhibitors of cytochrome P-450 epoxygenase (CYPE) or protein kinase C (PKC) but not by concomitant treatment with either SOD, a mast cell stabilizer, or inhibitors of nitric oxide synthase, cyclooxygenase, xanthine oxidase, NADPH oxidase, or platelet-activating factor. Immunoneutralizing P-selectin or intercellular adhesion molecule-1 (ICAM-1) completely prevented bradykinin-induced leukocyte adhesion and emigration but did not affect VPL. On the other hand, stabilization of F-actin with phalloidin prevented bradykinin-induced leukocyte emigration and VPL but did not alter leukocyte adhesion. These data indicate that bradykinin induces LECA in rat mesenteric venules via a B(2)-receptor-initiated, CYPE-, oxidant- and PKC-mediated, P-selectin- and ICAM-1-dependent mechanism. Bradykinin also produced VPL, an effect that was initiated by stimulation of B(2) receptors and involved CYPE and PKC activation, oxidant generation, and cytoskeletal reorganization but was independent of leukocyte adherence and emigration.
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PMID:Bradykinin-induced proinflammatory signaling mechanisms. 1238 46

Numerous studies in the literature have employed gene-modified mice to investigate vascular function. However, only very limited information exists on baseline murine vascular physiology or on potential variations between different strains. We therefore compared coronary and aortic vascular responses to endothelium-derived vasodilators and exogenous nitric oxide (NO) in three commonly used mouse strains and correlated these data with expression of eNOS, NADPH oxidase subunits, gp91(phox) and p67(phox), and superoxide production. Isolated perfused hearts from MF1, 129sv and C57BL/6J mice were subjected to: (a) increasing doses of bradykinin, acetylcholine and sodium nitroprusside, and (b) bolus doses of adenosine and the NO synthase inhibitor, N(G)-monomethyl- L -arginine. Vascular responses of thoracic aortic rings were assessed for comparison. Expression of eNOS and NADPH oxidase subunits was assessed by immunoblotting, and superoxide production by lucigenin-enhanced chemiluminescence. Coronary vasodilator responses to bradykinin, acetylcholine and sodium nitroprusside were significantly attenuated in MF1 compared with C57BL/6J and 129sv hearts. Similarly, aortic relaxation to acetylcholine was significantly impaired in MF1 aortic rings compared with in C57BL/6J aortae; these differences were reversed by Tiron. N(G)-monomethyl- L -arginine induced significantly less vasoconstriction in MF1 and 129sv hearts compared with C57BL/6J. No differences in aortic relaxation to A23187 or sodium nitroprusside were observed. Cardiac and aortic superoxide production and cardiac expression of p67(phox) and gp91(phox) were significantly greater in MF1 mice compared with the other strains. There is significant strain-dependent variation in coronary and aortic vascular responsiveness in mice, which may reflect differences in the balance between NO and superoxide generation.
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PMID:Strain-dependent variation in vascular responses to nitric oxide in the isolated murine heart. 1239 85

The NO/superoxide (O2-) balance is a key regulator of endothelial function. O2- levels are elevated in many forms of cardiovascular disease; therefore, decreasing O2- should improve endothelial function. To explore this hypothesis, internal mammary arteries and saphenous veins, obtained from patients undergoing coronary artery revascularization, and aortic and carotid arteries from Wistar-Kyoto and spontaneously hypertensive stroke-prone rats were incubated with O2- dismutase or NAD(P)H oxidase inhibitors. O2- levels were measured using lucigenin chemiluminescence; NO bioavailability was assessed in organ chambers; and mRNA expression of NAD(P)H oxidase components was quantified by use of a Light Cycler. In rat arteries, phenylarsine oxide, 4-(2-aminoethyl)-benzenesulfanyl fluoride, and apocynin all decreased NADH-stimulated O2- production, but only apocynin increased NO bioavailability. In human internal mammary arteries and saphenous veins, apocynin decreased NAD(P)H-stimulated O2- generation and caused vasorelaxation that was endothelium dependent and reversed on addition of the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester. In addition, it increased NO production from cultured human endothelial saphenous vein cells. Polyethylene-glycolated O2- dismutase also increased NO bioavailability in rat carotid arteries and human blood vessels, but the effects were smaller than those observed with apocynin. NADH-generated O2- and mRNA expression of p22(phox), gp91(phox), and nox-1 were comparable between the 2 strains of rat. This is the first study to demonstrate pharmacological effects of apocynin in human blood vessels. The increases in NO bioavailability shown here suggest that the NAD(P)H oxidase pathway may be a novel target for drug intervention in cardiovascular disease.
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PMID:NAD(P)H oxidase inhibition improves endothelial function in rat and human blood vessels. 1241 73

We tested the hypothesis that ceramide induces endothelial dysfunction in small coronary arteries via NADPH oxidase-mediated superoxide and resulting peroxynitrite formation. With the use of dihydroethidium as a superoxide indicator, C(2)-ceramide was found to increase superoxide production in the endothelial cells of small coronary arteries, which was inhibited by the NADPH oxidase inhibitors N-vanillylnonanamide, apocynin, and diphenylene iodonium. NADPH oxidase expression was confirmed in endothelial cells, as indicated by the immunoblotting of its subunits gp91(phox) and p47(phox). C(2)-ceramide increased NADPH oxidase activity by 52%, which was blocked by NADPH oxidase inhibitors but not by inhibitors of NO synthase, xanthine oxidase, and mitochondrial electron transport chain enzymes. By Western blot analysis, ceramide-induced NADPH oxidase activation was found to be associated with the translocation of p47(phox) to the membrane. In isolated and pressurized small coronary arteries, N-vanillylnonanamide, apocynin, or uric acid, a peroxynitrite scavenger, largely restored the inhibitory effects of ceramide on bradykinin- and A-23187-induced vasorelaxation. With the use of nitrotyrosine as a marker, C(2)-ceramide was found to increase peroxynitrite in small coronary arteries, which could be blocked by uric acid. We conclude that NADPH oxidase-mediated superoxide production and subsequent peroxynitrite formation mediate ceramide-induced endothelial dysfunction in small coronary arteries.
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PMID:Ceramide-induced activation of NADPH oxidase and endothelial dysfunction in small coronary arteries. 1242 96

Reactive oxygen species have an important pathogenic role in organ damage. We investigated the role of oxidative stress via nicotinamide adenine dinucleotide phosphate (NAD[P]H) oxidase in the kidney of the Dahl salt-sensitive (DS) rats with heart failure (DSHF). Eleven-week-old DS rats fed an 8%-NaCl diet received either vehicle or imidapril (1 mg/kg per day) for 7 weeks. The renal expression of the NAD(P)H oxidase p47phox and endothelial NO synthase were evaluated. In DSHF rats, associated with increased renal angiotensin II, mRNA and protein expression of NAD(P)H oxidase p47phox were enhanced with an increase in renal lipid peroxidation production (0.33+/-0.03 versus 0.22+/-0.01 nmol/mg protein, P<0.05) and urinary excretion of hydrogen peroxide (26.9+/-6.6 versus 9.5+/-2.1 U/mg creatinine, P<0.01) compared with levels in Dahl salt-resistant rats. The endothelial NO synthase expression was decreased in the kidney. Treatment with imidapril reduced renal angiotensin II and NAD(P)H oxidase expression and the oxidative products (kidney lipid peroxidation product: 0.16+/-0.02, P<0.001; urinary hydrogen peroxide: 3.1+/-0.2, P<0.01 versus DSHF rats). Imidapril significantly decreased albuminuria and reduced glomerulosclerosis without changes in the blood pressure. In conclusion, DSHF rats showed increased oxidative stress in the kidney via NAD(P)H oxidase. Blockade of local angiotensin II with subpressor dose of imidapril inhibited NAD(P)H oxidase and prevented renal damage.
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PMID:Angiotensin II and oxidative stress in Dahl Salt-sensitive rat with heart failure. 1246 66

Previously, we have demonstrated that increased superoxide generation plays a role in the nitric oxide (NO)-mediated inhibition of endothelial NO synthase (NOS III) in endothelial cells (ECs). In this study we demonstrate that the source of the superoxide is likely due to both NADPH oxidase and NOS III itself. Further, this increase appears to be linked to the activation of PKC, as PMA could mimic the increase and PKC inhibition ameliorate the increase. To further investigate this phenomenon we determined the effect of overexpression of copper-zinc superoxide dismutase (CuZn-SOD) and Manganese-SOD (Mn-SOD) on the inhibitory effects of NO. Using adenoviral infection we demonstrated that SOD activity was increased and superoxide levels decreased, in both CuZn-SOD and Mn-SOD overexpressing cells compared to cells infected with an adenovirus expressing bacterial beta-galactosidase protein. However, only the CuZn-SOD overexpression reduced the NO-mediated inhibition of NOS III. In addition, the level of NO-induced peroxynitrite generation and nitrated NOS III protein were reduced only in the CuZn-SOD overexpressing cells. In conclusion, our results indicate that superoxide and peroxynitrite are involved in the inhibition of NOS III by NO, and that the scavenging of superoxide may be necessary to prevent NOS III inhibition during treatments that involve inhaled NO or NO donors.
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PMID:The overexpression of copper-zinc superoxide dismutase protects NOS III from nitric oxide-mediated inhibition. 1248 93

Common vascular disease states including diabetes, hypertension and atherosclerosis are associated with endothelial dysfunction, characterised by reduced bioactivity of nitric oxide (NO). Loss of the vasculoprotective effects of NO contributes to disease progression, but the mechanisms underlying endothelial dysfunction remain unclear. Increased superoxide production in animal models of vascular disease contributes to reduced NO bioavailability, endothelial dysfunction and oxidative stress. In human blood vessels, the NAD(P)H oxidase system is the principal source of superoxide, and is functionally related to clinical risk factors and systemic endothelial dysfunction. Furthermore, the C242T polymorphism in the NAD(P)H oxidase p22phox subunit is associated with significantly reduced superoxide production in patients carrying the 242T allele, suggesting a role for genetic variation in modulating vascular superoxide production. In vessels from patients with diabetes mellitus, endothelial dysfunction, NAD(P)H oxidase activity and protein subunits are significantly increased compared with matched non-diabetic vessels. Furthermore, the vascular endothelium in diabetic vessels is a net source of superoxide rather than NO production, due to dysfunction of endothelial NO synthase (eNOS). This deficit is dependent on the eNOS cofactor, tetrahydrobiopterin, and is in part mediated by protein kinase C signalling. These studies suggest an important role for both the NAD(P)H oxidases and endothelial NOS in the increased vascular superoxide production and endothelial dysfunction in human vascular disease states.
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PMID:Mechanisms of superoxide production in human blood vessels: relationship to endothelial dysfunction, clinical and genetic risk factors. 1251 89

Iron- or copper-mediated catalysis leads to the generation of reactive oxygen species (ROS) that can attack biomolecules directly, with the consequent enhancement in membrane lipid peroxidation, DNA damage, and protein oxidation. Reactive nitrogen species (RNS) can also be formed, leading to nitration of aromatic structures in addition to the oxidative deterioration of cellular components. Kupffer cells, the resident macrophages of the liver, play significant roles in immunomodulation, phagocytosis, and biochemical attack. Upon stimulation, liver macrophages release biologically active products related to cell injury, namely, ROS, RNS, and both immunomodulatory and fibrogenic cytokines, with production of chemokines and adhesion molecules by other cells of the liver sinusoid. Iron and copper alter the functional status of Kupffer cells by enhancing their respiratory burst activity without modifying particle phagocytosis. This effect is probably due to extra O2 equivalents used in the oxidation of biomolecules and/or in the activating action of iron/copper on nitric oxide synthase, in addition to those employed by NADPH oxidase activity. Changes in gene expression of Kupffer cells may also be accomplished by iron and copper through modulation of the activity of transcription factors such as NF-kappaB, which signals the production of cytotoxic, proinflammatory, or fibrogenic mediators. Thus, iron/copper-induced hepatotoxicity is a multifactorial phenomenon underlying actions due to the generation of ROS and RNS that may alter essential biomolecules with loss of their biological functions, modulate gene expression of Kupffer cells with production of cytotoxic mediators, or both.
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PMID:Oxidative stress-mediated hepatotoxicity of iron and copper: role of Kupffer cells. 1257 70

Angiotensin II (Ang II) is a potent vasoconstrictor in the peripheral circulation and has been implicated in many cardiovascular diseases associated with elevated oxidative stress. However, its direct vasomotor action and its linkage to oxidative stress-induced vascular dysfunction in the coronary microcirculation remain elusive. In this study, we directly assessed the vasomotor action of Ang II in isolated porcine coronary arterioles and also examined whether Ang II can modulate endothelium-dependent nitric oxide (NO)-mediated dilation via superoxide production. Ang II evoked vasoconstriction at a low concentration (1 nmol/L) and dilations at higher concentrations (>10 nmol/L). Ang II type 1 (AT(1)) receptor antagonist losartan abolished vasoconstriction, whereas Ang II type 2 (AT(2)) receptor antagonist PD 123319 eliminated vasodilation. Adenosine stimulated a significant arteriolar NO production and dilation. NO synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA) abolished stimulated NO production and attenuated vasodilation. Pretreating vessels with a subvasomotor concentration of Ang II (0.1 nmol/L, 60 minutes) mimicked inhibitory effects of L-NMMA. Ang II-mediated inhibition was not observed in the presence of L-NMMA or after endothelial removal but was prevented by losartan, superoxide scavenger TEMPOL, or NADPH oxidase inhibitor apocynin. Dihydroethidium staining showed that Ang II elicited losartan- and TEMPOL-sensitive superoxide production in arterioles. These results demonstrate that Ang II evokes AT1 receptor-mediated vasoconstriction and AT2 receptor-mediated vasodilation of coronary arterioles. Ang II at a subvasomotor level impairs endothelium-dependent NO-mediated dilation attributable to elevated superoxide production via AT1 receptor activation of NADPH oxidase. These data may partly explain the impaired coronary flow regulation in heart diseases associated with an upregulated renin-angiotensin system.
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PMID:Divergent roles of angiotensin II AT1 and AT2 receptors in modulating coronary microvascular function. 1259 45


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