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)

Human saphenous veins (SV) are used for coronary bypass surgery despite the higher rate of graft failure observed as compared to arteries. A higher production of reactive oxygen species (ROS) in SV than in internal mammary artery (IMA) has been incriminated as possibly implicated in graft failure. NADPH oxidase, involved in vascular ROS production, was therefore characterized in human smooth muscle cells from SV. ROS production was confirmed to be essentially NADPH oxidase dependent in cultured smooth muscle cells (SMC) from human SV and increased in comparison with IMA. To investigate the role of NADPH oxidase subunits, siRNA for nox1, nox2, or p47 mRNA were studied. In cultured venous SMC under unstimulated conditions, inhibition of nox1 or nox2 mRNA decreased ROS production, whereas p47 silencing increased it. During angiotensin II (AngII) activation, nox2 or p47 mRNA silencing decreased ROS production, while nox1 inhibition had no effect. Venous SMC express functional nox1 and nox2. Only nox2 is implicated in response to AngII whilst nox1 is involved in unstimulated ROS production. p47 negatively regulates ROS generation under basal conditions, whereas it enhances AngII increased ROS production. Thus, nox1, nox2, and p47 have distinct roles in NADPH oxidase activity in human veins.
J Cardiovasc Pharmacol 2008 Feb
PMID:Distinct role of nox1, nox2, and p47phox in unstimulated versus angiotensin II-induced NADPH oxidase activity in human venous smooth muscle cells. 1828 80

Oxidative stress and inflammation processes are key components of atherosclerosis, from fatty streak formation to plaque rupture and thrombosis. Evidence has revealed that calcium-channel blockers (CCB) could retard atherogenesis, but the exact mechanisms have not been fully elucidated. The present study was undertaken to investigate the potential effects and molecular mechanisms of the CCB felodipine on the process of atherosclerosis in high-cholesterol-diet (HCD) apolipoprotein E-knockout (ApoE KO) mice. Adult male ApoE KO mice were given a normal diet (ND) or HCD and were randomized to no treatment or felodipine (5 mg / kg per day for 12 weeks). The ApoE KO mice with HCD were associated with a marked increase in plasma lipid levels, atherosclerotic lesion area, and the expressions of NADPH oxidase subunits (p47 and Rac-1), nuclear factor-kappaB (NF-kappaB) in nucleus, phosphor-inhibitors of kappaB (p-IkappaB), tumor necrosis-alpha (TNF-alpha), monocyte chemoattractant protein-1 (MCP-1), and vascular cell-adhesion molecule-1 (VCAM-1). These changes were suppressed in mice that were treated with felodipine (5 mg/kg per day for 12 weeks) concomitant with HCD administration, with no significant change in systolic blood pressure and plasma lipid levels. The results suggest that felodipine can attenuate atherosclerosis, and this effect is partly related to inhibition of oxidative stress and inflammatory signal-transduction pathways, which lead to decreases in the expression of inflammatory cytokines.
J Cardiovasc Pharmacol 2008 Feb
PMID:Molecular mechanisms of felodipine suppressing atherosclerosis in high-cholesterol-diet apolipoprotein E-knockout mice. 1828 87

Endothelial cells control vascular homeostasis by generating paracrine factors that regulate vascular tone, inhibit platelet function, prevent adhesion of leukocytes, and limit proliferation of vascular smooth muscle. The dominant factor responsible for many of those effects is endothelium-derived nitric oxide (NO). Endothelial dysfunction characterized by enhanced inactivation or reduced synthesis of NO, alone or in combination, is seen in conjunction with risk factors for cardiovascular disease. Endothelial dysfunction can promote vasospasm, thrombosis, vascular inflammation, and proliferation of the intima. Vascular oxidative stress and increased production of reactive oxygen species contributes to mechanisms of vascular dysfunction. Oxidative stress is mainly caused by an imbalance between the activity of endogenous pro-oxidative enzymes (such as NADPH oxidase, xanthine oxidase or the mitochondrial respiratory chain) and antioxidant enzymes (such as superoxide dismutase, glutathione peroxidase, heme oxygenase, thioredoxin peroxidase/peroxiredoxin, catalase and paraoxonase). In addition, small-molecular-weight antioxidants might have a role in the defense against oxidative stress. Increased concentrations of reactive oxygen species reduce bioactive NO through chemical inactivation, forming toxic peroxynitrite, which in turn can uncouple endothelial NO synthase to form a dysfunctional superoxide-generating enzyme that contributes further to oxidative stress. The role of oxidative stress in vascular dysfunction and atherogenesis, and strategies for its prevention are discussed.
Nat Clin Pract Cardiovasc Med 2008 Jun
PMID:Oxidative stress in vascular disease: causes, defense mechanisms and potential therapies. 1846 Oct 48

An increase in reactive oxygen species (ROS) through NADPH oxidase activation frequently follows stress that activates beta-adrenoreceptors, leading to deterioration of cardiovascular disease. We hypothesized that upregulation of NADPH oxidase in the vasculature causes mild vascular spasm subsequent to chronic isoproterenol (ISO) administration, correlating significantly with activation of both ETA and ETB receptors. We tested whether the dual endothelin receptor antagonist CPU0213 is effective in reversing ISO-induced vascular abnormality by suppressing activated NADPH oxidase in the vasculature. Rats were injected with ISO (1 mg/kg, SC) for 10 days to induce vascular dysfunction and treated with CPU0213 (30 mg/kg, SC) or aminoguanidine (AMG, an inhibitor of iNOS, 100 mg/kg, PO) from day 7 to day 10. On day 11, we found an increase in vascular response to phenylephrine (Phe) and reductions in NO availability and acetylcholine (ACh)-induced relaxation in ISO-treated rats along with upregulated mRNA of ETA, ETB, iNOS, NADPH oxidase-Phox22 and Phox47, and matrix metalloproteinase 9 (MMP9). These abnormalities were attenuated by 3 days of intervention with CPU0213 but less with AMG. CPU0213 was more effective in relieving enhanced vascular constriction and reversal of ET receptor and MMP9 expression in the vasculature than was AMG. In conclusion, an upregulation of NADPH oxidase phox 22 and phox 47, ETA and ETB, and MMP9 correlates with vascular abnormality and the endothelin receptor antagonist CPU0213 was more effective than AMG in reversing ISO-induced enhanced vascular constriction by normalizing the above abnormal expression.
J Cardiovasc Pharmacol 2008 Jul
PMID:The endothelin receptor antagonist CPU0213 is more effective than aminoguanidine to attenuate isoproterenol-induced vascular abnormality by suppressing overexpression of NADPH oxidase [correction of oxidas], ETA, ETB, and MMP9 in the vasculature. 1859 75

Diabetes activates atherogenesis and macrophage foam cell formation. This study's goal was to determine whether insulin counteracts diabetes-induced macrophage foam cell formation, as well as to determine transcriptional mechanisms involved in this effect.Insulin injection to diabetic mice reduced macrophage lipid peroxides levels, Ox-LDL uptake, and CD36 mRNA levels by 40%, 29%, and by 41% respectively, compared to age-matched untreated diabetic mice. These results were further assessed using an in vitro system. Addition of insulin to glucose-enriched cells led to a significant decrease in cellular lipid peroxidation by 43% compared to cells incubated with high concentrations of glucose with no insulin. This effect was correlated with a reduction in NADPH oxidase activity.Macrophage cholesterol biosynthesis was then studied in cells from diabetic mice treated with insulin and in glucose-enriched macrophages incubated with insulin. Insulin treatment of diabetic mice significantly reduced macrophage cholesterol biosynthesis, HMG-CoA reductase mRNA expression, and protein expression by 81%, 54%, and 31% respectively, compared to macrophages isolated from nontreated diabetic mice. Similarly, insulin incubation with glucose-enriched macrophages significantly reduced macrophage cholesterol biosynthesis, HMG-CoA reductase mRNA expression, and protein expression by 84%, 42%, and 18%, respectively, compared to macrophages incubated with high glucose but without insulin. These effects were mediated by glucose and insulin ability to regulate the transcription factor SREBP-1. Whereas glucose upregulated SREBP-1 expression and maturation, insulin blocked SREBP1 cleavage, leading to reduced mature form of the transcription factor in the nucleus.In conclusion, this study presents important novel insights on the events connecting diabetes and glucose stimulation of macrophage foam cell formation leading to atherosclerosis. Most important, the inhibitory effects of insulin on diabetes-mediated (and high glucose-induced) increased cholesterol synthesis were shown to involve modulation of SREBP-1 expression and its maturation.
J Cardiovasc Pharmacol 2008 Oct
PMID:High glucose concentration increases macrophage cholesterol biosynthesis in diabetes through activation of the sterol regulatory element binding protein 1 (SREBP1): inhibitory effect of insulin. 1879 64

Endothelial injury is thought to play a pivotal role in the development and progression of vascular diseases, such as atherosclerosis, hypertension or restenosis, as well as their complications, including myocardial infarction or stroke. Accumulating evidence suggests that bone marrow-derived endothelial progenitor cells (EPCs) promote endothelial repair and contribute to ischemia-induced neovascularization. Coronary artery disease and its risk factors, such as diabetes, hypercholesterolemia, hypertension and smoking, are associated with a reduced number and impaired functional activity of circulating EPCs. Moreover, initial data suggest that reduced EPC levels are associated with endothelial dysfunction and an increased risk of cardiovascular events, compatible with the concept that impaired EPC-mediated vascular repair promotes progression of vascular disease. In this review we summarize recent data on the effects of pharmacological agents on mobilization and functional activity of EPCs. In particular, several experimental and clinical studies have suggested that statins, angiotensin-converting enzyme inhibitors, angiotensin II type 1 receptor blockers, PPAR-gamma agonists and erythropoietin increase the number and functional activity of EPCs. The underlying mechanisms remain largely to be defined; however, they likely include activation of the PI3-kinase/Akt pathway and endothelial nitric oxide synthase, as well as inhibition of NAD(P)H oxidase activity of progenitor cells.
Expert Rev Cardiovasc Ther 2008 Sep
PMID:Pharmacological approaches to improve endothelial repair mechanisms. 1879 10

Diabetes can cause a wide variety of vascular complications and endothelial dysfunction. In this study, human vascular endothelial cells were exposed to 5.5 mM and 33 mM glucose for 5 d in the absence and presence of 1 to 20 mug/mL roasted licorice (Glycyrrhiza inflata Bat.) ethanol extracts (rLE). Caspase-3 activation and Annexin V staining revealed that high glucose induced endothelial apoptotic toxicity with a generation of reactive oxygen species (ROS) and these effects were reversed by rLE at >/=1 mug/mL in a dose-dependent manner. Cytoprotective rLE substantially reduced high glucose-induced expression of endothelial nitric oxide synthase (eNOS), and hence attenuated the formation of peroxynitrite radicals derived from NO. In addition, rLE suppressed expression of PKCbeta2 and activation of NADPH oxidase subunit of p22phox promoted by high glucose. However, rLE </=1 mug/mL did not modulate the high glucose-triggered activation of ASK-JNK signaling pathway. Our results suggest that PKCbeta2 expression and NADPH oxidase-dependent superoxide production and eNOS-mediated peroxynitrite generation may be essential mechanisms responsible for increased oxidative stress and endothelial apoptosis in chronic hyperglycemic conditions. Thus, rLE may be a beneficial agent most likely contributing to prevention of vascular NADPH oxidase induction and preservation of endothelial nitric oxide availability, resulting in blunting diabetes-associated endothelial dysfunction and vascular complications.
J Cardiovasc Pharmacol 2008 Oct
PMID:Blockade of nitroxidative stress by roasted licorice extracts in high glucose-exposed endothelial cells. 1884 Oct 76

The endothelium synthesizes and releases several vasodilator substances, including prostacyclin, nitric oxide (NO), and endothelium-derived hyperpolarizing factor (EDHF). We have demonstrated that endothelium-derived hydrogen peroxide (H2O2) is an EDHF in animals and humans and that superoxide anions derived from endothelial nitric oxide synthases (NOSs) system are an important precursor for EDHF/H2O2 in mice. There are several intracellular sources of superoxide anions other than NOSs, including NAD(P)H oxidase, xanthine oxidase, lipoxygenase, and mitochondrial electron transport chain. In this study, we examined the possible role of endothelial oxidases other than NOSs in the EDHF-mediated responses. In angiotensin II-infused mice, both EDHF-mediated relaxations and hyperpolarizations to acetylcholine were significantly reduced, nitric oxide-mediated relaxations were rather enhanced, and vascular smooth muscle responses were preserved. Antihypertensive treatment normalized blood pressure but failed to improve EDHF-mediated responses in those mice. Acute inhibition of endothelial oxidases other than NOSs, including NAD(P)H oxidase, xanthine oxidase, lipoxygenase, or mitochondrial electron transport chain, had no inhibitory effects on EDHF-mediated responses. Furthermore, in p47phox-knockout mice, EDHF-mediated responses were unaltered. These results suggest that endothelial oxidases other than NOSs are not involved in EDHF/H2O2 responses in mice, suggesting a specific link between endothelial NOSs system and EDHF responses under physiological conditions.
J Cardiovasc Pharmacol 2008 Dec
PMID:Roles of endothelial oxidases in endothelium-derived hyperpolarizing factor responses in mice. 1903 34

Oxidative stress mediated by hyperglycaemia-induced generation of reactive oxygen species (ROS) contributes significantly to the development and progression of diabetes and related vascular complications. NAD(P)H oxidase has been implicated as the major source of ROS generation in the vasculature in response to high glucose and advanced glycation end-products. Sustained activation of NAD(P)H oxidase in diabetes may diminish intracellular levels of NADPH, an essential cofactor for endothelial NO synthase (eNOS) and several antioxidant systems. Recent evidence suggests that basal ROS production via NAD(P)H oxidase may upregulate antioxidant enzyme defenses via redox signalling. Thus, NAD(P)H oxidase may serve as a double-edged sword, with transient activation providing a feedback defense against excessive ROS generation through the activation of receptor tyrosine kinases and the redox-sensitive Nrf2-Keap1 signalling pathway. Overproduction of ROS leads to eNOS uncoupling, mitochondrial dysfunction, and impaired antioxidant defenses owing to depletion of intracellular NADPH. Given the largely negative outcome of antioxidant therapy in the treatment of diabetic complications, targeting the redox-sensitive transcription factor Nfr2 may provide an effective strategy to restore antioxidant defenses in diabetes.
Cardiovasc Res 2009 Apr 01
PMID:Vascular NAD(P)H oxidase activation in diabetes: a double-edged sword in redox signalling. 1917 52

Oxidative stress produced through reactive oxygen species (ROS) enhancement is considered to play a key role in the development and maintenance of hypertension. In the vasculature, the most important source of ROS is the reduced nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase enzyme. The principal stimulus of this enzyme is angiotensin II (Ang II). However, oxidative stress seems to be present in virtually all forms of hypertension including low-renin hypertension, where the levels of Ang II are reduced. For this reason, the question is if ROS generation is induced by Ang II or it is a consequence of hypertension. We used as hypertensive model the aortic coarctated rats, which were treated with losartan or minoxidil for 7 days. Thoracic aortic segments were excised, and the NAD(P)H oxidase subunits expression, oxidative stress parameters, and heme oxygenase-1 abundance were evaluated. Hypertensive animals had an increase in the activity and expression of NAD(P)H oxidase and, as a consequence, in the oxidative stress parameters. Interestingly, either losartan or minoxidil administration blunted those parameters, indicating that arterial pressure is the key factor in the development of oxidative stress in the hypertensive aorta. We suggest that antihypertensive drug administration at the beginning of this pathology delays the oxidative stress generation, thus preventing the aggravation of this disease.
J Cardiovasc Pharmacol 2009 Oct
PMID:Lowering arterial pressure delays the oxidative stress generation in a renal experimental model of hypertension. 1968 45


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