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

---

Query: EC:1.6.3.1 (NADPH oxidase)
11,281 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously reported that ANG II stimulation increased superoxide anion (O2-) through the activation of NAD(P)H oxidase and inhibited nitric oxide (NO)-dependent control of myocardial oxygen consumption (MVo2) by scavenging NO. Our objective was to investigate the role of NAD(P)H oxidase, especially the gp91phox subunit, in the NO-dependent control of MVo2. MVo2 in mice with defects in the expression of gp91phox [gp91(phox)(-/-)] was measured with a Clark-type oxygen electrode. Baseline MVo2 was not significantly different between wild-type (WT) and gp91(phox)(-/-) mice. Stimulation of NO production by bradykinin (BK) induced significant decreases in MVo2 in WT mice. BK-induced reduction in MVo2 was enhanced in gp91(phox)(-/-) mice. BK-induced reduction in MVo2 in WT mice was attenuated by 10(-8) mol/l ANG II, which was restored by coincubation with Tiron or apocynin. In contrast to WT mice, BK-induced reduction in MVo2 in gp91(phox)(-/-) mice was not altered by ANG II. There was a decrease in lucigenin (5 x 10(-6) mol/l)-detectable O2- in gp91(phox)(-/-) mice compared with WT mice. ANG II resulted in significant increases in O2- production in WT mice, which was inhibited by coincubation with Tiron or apocynin. However, ANG II had no effect on O2- production in gp91(phox)(-/-) mice. Histological examination showed that the development of abscesses and/or the invasion of inflammatory cells occurred in lungs and livers but not in hearts and kidneys from gp91(phox)(-/-) mice. These results indicate that the gp91(phox) subunit of NAD(P)H oxidase mediates O2- production through the activation of NAD(P)H oxidase and attenuation of NO-dependent control of MVo2 by ANG II.
...
PMID:gp91phox-containing NAD(P)H oxidase mediates attenuation of nitric oxide-dependent control of myocardial oxygen consumption by ANG II. 1577 77

Vascular inflammation is involved in the initiation and progression of atherosclerosis, and is also present in hypertension- and diabetes-induced vascular complications. Angiotensin II (Ang II), the key effector of the renin-angiotensin system (RAS), plays a central role in the regulation of blood pressure and electrolyte homeostasis. There is accumulating evidence to indicate that Ang II is also capable of inducing inflammatory response in the vascular wall. This review summarizes the current understanding of the molecular mechanisms and signal transduction pathways of Ang II-induced vascular inflammation. The roles of modulators of Ang II-induced inflammatory response, such as nitric oxide (NO), bradykinin, cyclooxygenase-2 (COX-2), endothelin-1 (ET-1), and epoxyeicosatrienoic acids (EETs), are also discussed. The current data suggest that Ang II modifies several steps of inflammatory response, such as increase of vascular permeability, leukocyte infiltration, tissue hypertrophy/proliferation, and fibrosis. Ang II, via the type 1 (AT1) receptors, enhances the production of reactive oxygen species (ROS) through stimulation of NAD(P)H oxidase in the vascular wall. Increased oxidative stress contributes to endothelial dysfunction and to vascular inflammation by stimulating the redox-sensitive transcription factors (NF-kappaB) and by upregulating adhesion molecules, cytokines, and chemokines. The pro-inflammatory action of Ang II may help us to understand the molecular mechanisms of hypertension- and diabetes-induced vascular complication as well as the pleiotropic actions of drugs interfering with RAS.
...
PMID:Angiotensin II and vascular inflammation. 1591 31

Human inflammatory bowel diseases (IBD) are associated with significant alterations in intestinal blood flow, the direction and magnitude of which change with disease progression. The objectives of this study were to determine the time course of changes in colonic blood perfusion that occur during the development of dextran-sodium-sulfate (DSS)-induced colonic inflammation and to address the mechanisms that may underlie these changes in blood flow. Intravital microscopy was used to quantify blood flow (from measurements of vessel diameter and red blood cell velocity) in different-sized submucosal arterioles of control and inflamed colons in wild-type (WT) mice. A significant (18-30%) reduction in blood flow was noted in the smallest arterioles (<40 microm diameter) on days 4-6 of DSS colitis. The arteriolar responses to bradykinin in control and DSS-treated WT mice revealed an impaired endothelium-dependent, but not endothelium-independent, vasodilation in the inflamed colon. However, this impaired vasodilatory response to bradykinin after DSS treatment was not evident in mutant mice that overexpress Cu,Zn-superoxide dismutase. Rescue of the bradykinin-induced vasodilation during DSS colitis was also observed in mice that are genetically deficient in the NAD(P)H oxidase subunit gp91(phox). These findings indicate that the decline in blood flow during experimental colitis may result from a diminished capacity of colonic arterioles to respond to endogenous endothelium-dependent vasodilators like bradykinin and that NAD(P)H oxidase-derived superoxide plays a major role in the induction of the inflammation-induced endothelium-dependent arteriolar dysfunction.
...
PMID:Colonic blood flow responses in experimental colitis: time course and underlying mechanisms. 1608 59

To elucidate the molecular mechanisms of the cardioprotective effect of angiotensin-converting enzyme (ACE) inhibitors, we evaluated whether the effect of quinapril involved in bradykinin-endothelial nitric oxide synthase (eNOS) and oxidative stress-lectin-like oxidized LDL receptor-1 (LOX-1) pathway. Dahl salt-sensitive hypertensive (DS) rats were fed a diet containing 8% NaCl and treated with one of the following drug combinations for 5 weeks, from 6 weeks of age to left ventricular hypertrophy stage (11 weeks): vehicle; quinapril; quinapril plus the bradykinin B2 receptor antagonist FR172357; the NAD(P)H oxidase inhibitor apocynin; or quinapril plus apocynin. eNOS expression, which was decreased in hypertrophy stage, was significantly increased by quinapril and/or apocynin, but not by quinapril plus FR172357. Upregulated expression of NAD(P)H oxidase p22phox, p47phox, gp91phox and LOX-1 was significantly decreased by quinapril to a similar degree as after treatment with apocynin, but not by quinapril plus FR172357. Quinapril and/or apocynin treatment effectively ameliorated left ventricular weight and vascular changes such as increase in medial thickness and perivascular fibrosis and suppressed expression of transforming growth factor-beta1, type I collagen and fibronectin mRNA, but not that of quinapril plus FR172357. These results suggest that the ACE inhibitor quinapril may have cardioprotective effects in this model of hypertension mediated at least in part through effects on the bradykinin-eNOS and oxidative stress-LOX-1 pathway.
...
PMID:Critical role of bradykinin-eNOS and oxidative stress-LOX-1 pathway in cardiovascular remodeling under chronic angiotensin-converting enzyme inhibition. 1621 49

The effects of dihydropyridine Ca2+ channel blockers (DHP) and ACE inhibitors on superoxide formation and nitric oxide (NO) bioavailability were compared in human EA.Hy926 endothelial cells (EC). EC were stimulated 4 h with angiotensin II (Ang II, 10 nM) +/- study drugs. Specific superoxide formation was measured by lucigenin-enhanced chemiluminescence, reduction of cytochrome c and rhodamine-123 fluorescence. Free NO release was determined with an amperometric NO sensor. NADPH oxidase subunits expression was examined with Western Blot. In untreated EC the intracellular superoxide is -64.3 +/- 6.0% decreased compared to Ang II stimulated EC. Elevated extracellular superoxide formation was on a -43.0 +/- 1.7% lower level in untreated EC. The DHP Ca2+-channel agonist BayK8644 and ACE inhibitors captopril and ramiprilat led extracellular superoxide concentration to control level. Enalaprilat blocked extracellular superoxide, the DHP amlodipine and nisoldipine prevented intracellular increases only (n = 8-9, p < 0.05). Icatibant (HOE 140), a kinin-B2 receptor antagonist, attenuated antioxidant actions of all tested agents except of nisoldipine. Ang II-induced superoxide was elevated by the phorbolester PMA and blocked by the protein kinase C (PKC) inhibitor chelerythrine. Suppression of substance P-evoked NO release by Ang II (>70%, n = 6) was reversed by the PKC inhibitor chelerythrine, the DHP amlodipine and nisoldipine and the ACE inhibitor ramiprilat. Further, Ang II reduces Nox-4 expression by 34.5 +/- 4.9. Nox-2 expression was not regulated. DHP and ACE inhibitors exert different antioxidant effects in human EC stimulated with Ang II, but both improve NO bioavailability via bradykinin and modulation of redox-regulating enzymes.
...
PMID:Antioxidant and nitric oxide-sparing actions of dihydropyridines and ACE inhibitors differ in human endothelial cells. 1622 25

We previously reported that reactive oxygen species (ROS) in paraventricular nucleus (PVN) modulated cardiac sympathetic afferent reflex (CSAR) and mediated the effect of angiotensin II (Ang II) in the PVN on the CSAR. In the present study, we investigated whether the NAD(P)H oxidase in the PVN was a key source of ROS which modulated the CSAR and contributed to the effect of Ang II on the CSAR. In anesthetized rats with sinoaortic denervation and vagotomy, renal sympathetic nerve activity (RSNA) and arterial pressure were recorded. The CSAR was evaluated by the RSNA response to epicardial application of bradykinin (BK). The NAD(P)H oxidase activity in the PVN was measured with lucigenin-enhanced chemiluminescent method. Microinjection of the NAD(P)H oxidase inhibitor, either apocynin (1.0 nmol) or phenylarsine oxide (PAO, 1.0 nmol), into the PVN significantly inhibited the CSAR. Microinjection of Ang II (0.3 nmol) into the PVN significantly augmented the CSAR. The effects of Ang II were not only abolished by pretreatment with either apocynin or PAO in the PVN but also partially inhibited by xanthine oxidase inhibitor allopurinol. Either epicardial application of BK or microinjection of Ang II into the PVN significantly increased NAD(P)H oxidase activity in the PVN. The effect of Ang II on NAD(P)H oxidase activity was abolished by pretreatment with AT(1) receptor antagonist losartan in the PVN. These findings suggested that NAD(P)H oxidase in the PVN was a major source of the ROS in modulating the CSAR, and the NAD(P)H oxidase contributes to the effect of Ang II on the CSAR.
...
PMID:NAD(P)H oxidase in paraventricular nucleus contributes to the effect of angiotensin II on cardiac sympathetic afferent reflex. 1651 80

In the failing heart, the local angiotensin II concentration is increased, and the extent of cardiac angiotensin II release is related to the clinical signs of heart failure. The enzymes involved in myocardial generation of angiotensin II are the angiotensin-converting enzyme (ACE) and chymases. While myocardial angiotensin II is mainly generated by chymases in the human heart, ACE inhibitors nevertheless improve left ventricular (LV) function, attenuate LV remodelling and reduce mortality in heart failure patients. These beneficial actions of ACE inhibitors, however, relate to their beneficial effect on kinin metabolism. Angiotensin II type 1 receptor (AT1) antagonists also mediate part of their beneficial effects through increased bradykinin formation. However, in contrast to ACE inhibitors, AT1 receptor antagonists attenuate downstream signalling of angiotensin II-induced AT1 receptor activation, which increases the activity of existing proteins (e.g. NADPH oxidase) and the de novo synthesis of proteins (e.g. inducible nitric oxide synthase, tumor necrosis factor-alpha ) in cardiomyocytes. Given the multiple actions of AT1 receptor activation on cardiomyocyte and non-cardiomyocyte function in the presence of an increased myocardial AngII concentration, the reduction of cardiovascular mortality and rate of hospitalization following AT1 receptor blockade in heart failure patients not receiving ACE inhibitors is not surprising. Most importantly, the beneficial effects of AT1 receptor blockade are not only achieved when used as an alternative to ACE inhibition, but also when used on top of ACE inhibitors.
...
PMID:Angiotensin II in the failing heart. Short communication. 1653 30

The development of nitrate tolerance has been found to be associated with vascular production of superoxide anion (O2-*), generated mainly by the eNOS and NADPH oxidase pathways. The aim of our study was to investigate whether long-term angiotensin-converting enzyme inhibition by ramipril is able to protect against nitrate tolerance in the aortas of eNOS-deficient (eNOS-/-) mice and to assess the implication of the NADPH oxidase pathway. Therefore, 3 types of treatment were given to wild-type (WT) and eNOS-/- mice: group 1 received ramipril for 5 weeks and a co-treatment with ramirpil plus nitroglycerine (NTG) during the last 4 days, group 2 received only NTG, and group 3 served as control. Relaxations to NTG (0.1 nmol/L to 0.1 mmol/L) were determined on U44619, a thromboxane analogue, precontracted rings, and O2-* production were assessed on aorta homogenates with the lucigenin-enhanced chemiluminescence technique. Cyclic guanosine monophosphate and reverse-transcriptase-polymerase chain reaction analyses were performed on whole mouse aortas. In WT group 2, the concentration-effect curves to NTG were significantly shifted to the right: the pD2 was 6.16 +/- 0.17 (n = 6) vs 6.81 +/- 0.10 (n = 6) in WT group 3 (not exposed to NTG; P < 0.05) and O2-* production was enhanced from 100% +/- 11% (n = 9) to 191% +/- 21% (n = 6; P < 0.01). In contrast, in WT group 1, the rightward shift was abolished: the pD2 value was 6.73 +/- 0.13 (n = 6; NS vs group 3 WT) and O2-* production was 117% +/- 6% (n = 7; NS vs group 3 WT). In eNOS groups 1 and 3, similar data were observed: the pD2 values were 7.58 +/- 0.08 and 7.38 +/- 0.11 (NS) vs 6.89 +/- 0.20 in eNOS group 2 (n = 6; P < 0.01). In the WT mice aortas, ramipril treatment significantly increased the cyclic guanosine monophosphate levels (reflecting nitric oxide availability), which returned to control values after in vivo co-treatment with a bradykinin BK2 antagonist (Icatibant). In both strains, candesartan, an AT1 blocker, was also able to protect against the development of nitrate tolerance. Moreover, before NTG exposure, ramipril treatment decreased p22phox and gp91phox (essential NADPH oxidase subunits) mRNA expression in aortas from both mice strains. In conclusion, long-term ramipril treatment in mice protects against the development of nitrate tolerance by counteracting NTG-induced increase in O2 production, which involves a direct interaction with the NADPH oxidase pathway and seems to be completely independent of the eNOS pathway.
...
PMID:Ramipril treatment protects against nitrate-induced oxidative stress in eNOS-/- mice: An implication of the NADPH oxidase pathway. 1689 13

Maternal malnutrition is known to impair fetal growth and predispose to the development of hypertension and type 2 diabetes. Recently, studies have demonstrated that intrauterine malnutrition is followed later in male offspring by oxidative stress characterized by increased superoxide generation due to activation of NADPH oxidase and reduced antioxidant defenses. However, few studies have investigated the mechanisms involved in endothelial dysfunction in female offspring. We evaluated the effects of the exogenous application of superoxide scavengers on the endothelium-dependent vasorelaxation in the mesenteric microvessels of female offspring. In addition, we examined indicative parameters of oxidative stress by measuring superoxide anion concentration and the activity of superoxide dismutase (SOD) as a marker of antioxidant defenses. Pregnant female Wistar rats were fed either a normal diet or 50% of this, throughout gestation. Intrauterine malnutrition induced hypertension and increased superoxide production without affecting SOD activity. Topical application of MnTMPyP (SOD mimetic) and apocynin (NADPH oxidase inhibitor) significantly improved the altered arteriolar responses to acetylcholine and bradykinin. In addition, incubation with apocynin reduced superoxide generation in these female offspring. The data suggest that after exposure to intrauterine malnutrition, female offspring present an increased superoxide production that is, at least in part, responsible for an endothelial dysfunction observed in these animals. These effects may be mediated via modulation of enzyme systems that generate superoxide.
...
PMID:Long-term effects of intrauterine malnutrition on vascular function in female offspring: implications of oxidative stress. 1715 80

Aging is associated with cerebrovascular dysregulation, which may underlie the increased susceptibility to ischemic stroke and vascular cognitive impairment occurring in the elder individuals. Although it has long been known that oxidative stress is responsible for the cerebrovascular dysfunction, the enzymatic system(s) generating the reactive oxygen species (ROS) have not been identified. In this study, we investigated whether the superoxide-producing enzyme NADPH oxidase is involved in alterations of neurovascular regulation induced by aging. Cerebral blood flow (CBF) was recorded by laser-Doppler flowmetry in anesthetized C57BL/6 mice equipped with a cranial window (age=3, 12, and 24 months). In 12-month-old mice, the CBF increases evoked by whisker stimulation or by the endothelium-dependent vasodilators acetylcholine and bradykinin were attenuated by 42, 36, and 53%, respectively (P<0.05). In contrast, responses to the nitric oxide donor S-nitroso-D-penicillamine or adenosine were not attenuated (P>0.05). These cerebrovascular effects were associated with increased production of ROS in neurons and cerebral blood vessels, assessed by hydroethidine microfluorography. The cerebrovascular impairment present in 12-month-old mice was reversed by the ROS scavenger Mn (III) tetrakis (4-benzoic acid) porphyrin chloride or by the NADPH oxidase peptide inhibitor gp91ds-tat, and was not observed in mice lacking the Nox2 subunit of NADPH oxidase. These findings establish Nox2 as a critical source of the neurovascular oxidative stress mediating the deleterious cerebrovascular effects associated with increasing age.
...
PMID:Nox2-derived reactive oxygen species mediate neurovascular dysregulation in the aging mouse brain. 1742 47


<< Previous 1 2 3 4 5 6 Next >>

---