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)

Current concepts of cellular oxygen-sensing include an isoform of the neutrophil NADPH oxidase, different electron carrier units of the mitochondrial electron transport chain (ETC), heme oxygenase-2 (HO-2), and a subfamily of 2-oxoglutarate dependent dioxygenases termed HIF (hypoxia inducible factor) prolyl hydroxylases (PHDs) and HIF asparagyl hydroxylase FIH-1 (factor-inhibiting HIF). Different oxygen sensitivities, cell-specific distribution and subcellular localization of specific oxygen-sensing cascades involving reactive oxygen species (ROS) as second messengers may help to tailor various adaptive responses according to differences in tissue oxygen availability. Herein, we propose an integrated model for these various oxygen-sensing mechanisms that very efficiently regulate HIF-alpha activity and plasma membrane potassium-channel (PMPC) conductivity.
Cardiovasc Res 2006 Jul 15
PMID:The good, the bad and the ugly in oxygen-sensing: ROS, cytochromes and prolyl-hydroxylases. 1674 Feb 53

Diseases such as hypertension, atherosclerosis and diabetes are associated with vascular functional and structural changes including endothelial dysfunction, altered contractility and vascular remodeling. Cellular events underlying these processes involve changes in vascular smooth muscle cell (VSMC) growth, apoptosis/anoikis, cell migration, inflammation, and fibrosis. Many stimuli influence cellular changes, including mechanical forces, such as shear stress, and vasoactive agents, of which angiotensin II (Ang II) appears to be amongst the most important. Ang II mediates many of its pleiotropic vascular effects through NAD(P)H oxidase-derived reactive oxygen species (ROS). Mechanical forces, comprising both unidirectional laminar and oscillatory shear, are increasingly being recognized as important inducers of vascular NO and ROS generation. In general, laminar flow is associated with upregulation of eNOS and NO production and increased expression of antioxidants glutathione peroxidase and superoxide dismutase, thereby promoting a healthy vascular wall and protecting against oxidative vascular injury. On the other hand, oscillatory shear is linked to increased ROS production with consequent oxidative damage, as occurs in hypertension. ROS function as important intracellular and intercellular second messengers to modulate many downstream signaling molecules, such as protein tyrosine phosphatases, protein tyrosine kinases, transcription factors, mitogen-activated protein kinases, and ion channels. Induction of these signaling cascades leads to VSMC growth and migration, expression of pro-inflammatory mediators, and modification of extracellular matrix. In addition, ROS increase intracellular free Ca(2+) concentration, a major determinant of vascular reactivity. ROS influence signaling molecules by altering the intracellular redox state and by oxidative modification of proteins. In physiological conditions, low concentrations of intracellular ROS play an important role in normal redox signaling involved in maintaining vascular function and integrity. Under pathological conditions ROS contribute to vascular dysfunction and remodeling through oxidative damage. The present review describes some of the redox-sensitive signaling pathways that are involved in the functional and structural vascular changes associated with hypertension.
Cardiovasc Res 2006 Jul 15
PMID:Redox signaling in hypertension. 1676 37

Reactive oxygen species (ROS) play a pivotal role in many physiological processes including host defense, hormone biosynthesis, fertilization and cellular signaling. Altered production of ROS has been implicated in the development of immunodeficiency, hypothyroidism and cardiovascular pathologies. In the last few years, several enzymes were identified at the molecular level, which are now thought to be responsible for ROS production observed in diverse tissues. These enzymes show a high degree of homology to the phagocytic NADPH oxidase and are now designated the Nox family of NADPH oxidases. This review updates our knowledge on six new members of the Nox family: Nox1, Nox3, Nox4, Nox5, Duox1 and Duox2.
Cardiovasc Res 2006 Jul 15
PMID:NADPH oxidases: new kids on the block. 1676 21

Angiogenesis, a process of new blood vessel formation, is a key process involved in normal development and wound repair as well as in the various pathophysiologies such as ischemic heart and limb diseases and atherosclerosis. Reactive oxygen species (ROS) such as superoxide and H(2)O(2) function as signaling molecules in many aspects of growth factor-mediated responses including angiogenesis. Vascular endothelial growth factor (VEGF) is a key angiogenic growth factor and stimulates proliferation, migration, and tube formation of endothelial cells (ECs) primarily through the VEGF receptor type2 (VEGR2, KDR/Flk1). VEGF binding initiates autophosphorylation of VEGFR2, which results in activation of downstream signaling enzymes including ERK1/2, Akt, and eNOS in ECs, thereby stimulating angiogenesis. The major source of ROS in EC is a NADPH oxidase which consists of Nox1, Nox2 (gp91phox), Nox4, p22phox, p47phox, p67phox and the small G protein Rac1. The endothelial NADPH oxidase is activated by angiogenic factors including VEGF and angiopoietin-1. ROS derived from this enzyme stimulate diverse redox signaling pathways leading to angiogenesis-related gene induction as well as EC migration and proliferation, which may contribute to postnatal angiogenesis in vivo. The aim of this review is to provide an overview of the recent progress on the emerging area of the role of ROS derived from NADPH oxidase and redox signaling in angiogenesis. Understanding these mechanisms may provide insight into the NADPH oxidase and redox signaling components as potential therapeutic targets for treatment of angiogenesis-dependent cardiovascular diseases and for promoting angiogenesis in ischemic limb and heart diseases.
Cardiovasc Res 2006 Jul 15
PMID:Redox signaling in angiogenesis: role of NADPH oxidase. 1678 92

Reactive oxygen species (ROS) are acknowledged generally to be multi-faceted regulators of cellular functions that trigger various pathological states when present chronically or transiently at non-physiologically high levels. Here we focus on the physiological involvement of ROS in cellular motility, with special emphasis on endothelial cells (EC). An important source of ROS within EC is the non-phagocytic NAD(P)H oxidase, and the small GTPase Rac1 plays a central role in activating this complex. Rac1 is one of the three Rho-family molecules (Rac, Rho and Cdc42) involved in the control of the actin cytoskeleton in response to various signals. In this review we examine the evidence linking ROS production, Rac1 activation and actin organization to EC motility, considering mechanisms for direct interaction of ROS and actin and the effects of ROS on proteins that regulate the actin cytoskeleton. The accumulated evidence suggests that ROS are important regulators of the actin cytoskeletal dynamics and cellular motility, and more in-depth studies are needed to understand the underlying mechanisms.
Cardiovasc Res 2006 Jul 15
PMID:Reactive oxygen species in vascular endothelial cell motility. Roles of NAD(P)H oxidase and Rac1. 1678 79

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.
J Cardiovasc Pharmacol 2006 Jul
PMID:Ramipril treatment protects against nitrate-induced oxidative stress in eNOS-/- mice: An implication of the NADPH oxidase pathway. 1689 13

Vascular aging is characterized by endothelial dysfunction that is primarily attributed to increased superoxide production, the exact source of which remains ambiguous. This study compared the NAD(P)H and xanthine oxidase (XO) systems as sources of superoxide and impaired vascular function in aging. Male Sprague Dawley rats, 4-months-old (young) and 18-months-old (Aging), were used. Systolic blood pressure was higher (36 +/- 3%) in the aging group compared with young rats, and this was accompanied by reduced acetylcholine-induced renal vasodilatation. Urinary excretion of nitrite was lower in the aging rats (P < 0.05), and this was associated with reduced nitric oxide synthase (NOS) activity and reduced eNOS and iNOS protein expression in the aorta. Aged rats showed a n approximately twofold increase in free radical generation, as evident by increased plasma 8-isoprostane level, and an approximately fourfold increase in proteinuria compared with the young rats. Vascular NADP(H) oxidase was unchanged between both groups, as was the expression of p67phox or p47phox components of NAD(P)H oxidase. However, XO activity was increased (19 +/- 1%; P < 0.05) as well as XO expression in the aorta of aging rats. These results suggest that increased free radical generation-associated increase in SBP in aging rats is XO but not NAD(P)H oxidase-dependent.
J Cardiovasc Pharmacol 2006 Sep
PMID:Oxidative stress-associated vascular aging is xanthine oxidase-dependent but not NAD(P)H oxidase-dependent. 1703 Dec 61

Oxidative stress plays an important role in the pathogenesis of diabetic complications, and we investigated the effect of superoxide dismutase (SOD) mimetic, tempol, in diabetic nephropathy. Streptozotocin-induced diabetic rats were treated with tempol from 2 weeks until 8 weeks. The expression of NADPH oxidase, catalase, and myeloperoxidase (MPO), superoxide dismutase activity, and production of peroxide and hypochlorite were evaluated. Tempol treatment prevented the increase in NADPH oxidase and peroxide production in the glomeruli of diabetic rat. Catalase was decreased without change in SOD activity, and MPO was enhanced in the kidney of diabetic rats. Tempol treatment stimulated SOD activity and increased the conversion of superoxide to hydrogen peroxide, and hydrogen peroxide on its hand was converted to hypochlorite by the increased MPO. The reduction of peroxide by tempol was followed by the decrease in TGF-beta and mesangial matrix expansion. However, tempol did not reduce hypochlorite or urinary protein excretion. In conclusion, tempol inhibited glomerular matrix expansion via suppression of peroxide production and TGF-beta, but it failed to reduce proteinuria, probably due to the increased hypochlorite production in diabetic nephropathy.
J Cardiovasc Pharmacol 2007 Jan
PMID:Double-edged action of SOD mimetic in diabetic nephropathy. 1726 58

Atherosclerosis is considered to be a chronic inflammatory disease. Vascular inflammation occurs in response to injury induced by various stimuli, such as oxidative stress, shear stress, infection, and so on. This concept is supported by the recent clinical findings that C-reactive protein (CRP) is an independent risk factor for coronary heart disease. CRP, which was originally identified as a protein that could precipitate the C-polysaccharide of pneumococcal cell walls, has been widely used as a clinical marker of the state of inflammation, since its production by hepatocytes increases during the acute phase of the inflammatory response. Recent investigations have provided two new concepts for the research field of CRP, namely, its extra-hepatic production and its potent biological activities such as the induction of adhesion molecules and chemokines. Recently, we demonstrated that smooth muscle cells and macrophages in coronary arteries expressed CRP protein and mRNA, as evaluated using coronary specimens of coronary artery disease (CAD) patients obtained by atherectomy. The expression of vascular CRP was closely associated with NAD(P)H oxidase, an important enzymatic origin of reactive oxygen species (ROS) in vessel walls. Furthermore, CRP directly up-regulated NAD(P)H oxidase p22(phox) and enhanced ROS generation in cultured coronary artery smooth muscle cells. Thus, vascular CRP is likely to be a direct participant in vascular inflammation and lesion formation via its potent biological effects. Since lysophosphatidylcholine, a major atherogenic lipid of oxidized LDL, was reported to activate vascular NAD(P)H oxidase, we speculate that there is a vicious circle consisting of vascular NAD(P)H oxidase, ROS and oxidized LDL. Since phagocytic NAD(P)H oxidase is at the first line of the host defense system, it is important to selectively suppress vascular NAD(P)H oxidase in the localized inflammatory lesions in therapeutic strategies for CAD. In this review, we will discuss the roles of vascular CRP and NAD(P)H oxidase in the pathogenesis of CAD from the viewpoint of oxidative stress.
Cardiovasc Hematol Disord Drug Targets 2006 Dec
PMID:Vascular C-reactive protein in the pathogenesis of coronary artery disease: role of vascular inflammation and oxidative stress. 1737 68

3-Hydroxyl-3-methylglutaryl coenzyme A reductase inhibitors (statins) may benefit the vasculopathy of insulin resistance independent of its lipid-lowering effects. Because imbalance of nitric oxide (NO) and superoxide anion (O(2)(-)) formation may lead to vascular dysfunction, we investigated the effect of statin on vasomotion of insulin-resistant state to clarify the mechanism by which statin ameliorates the impaired function. In the isolated aorta, contraction induced by angiotensin II was more potent in Zucker fatty rats (ZF) compared with that in Zucker lean rats. Both angiotensin II type 1 receptor expression and O(2)(-) production were upregulated in ZF. In addition, deficiency of tetrahydrobiopterin (BH4) contributes to the endothelial dysfunction in ZF. Oral administration of pitavastatin for 8 weeks normalized angiotensin II-induced vasoconstriction and endothelial function in ZF. Pitavastatin treatment of ZF increased vascular BH4 content, which was associated with twofold increase in endothelial NO synthase (eNOS) activity as well as a 60% reduction in endothelial O(2)(-) production. The treatment also markedly downregulated protein expression of angiotensin II type 1 receptor and gp91phox, whereas expression of guanosine triphosphate cyclohydrolase I was upregulated. Pitavastatin restores vascular dysfunction by inhibiting NAD(P)H oxidase activity and uncoupled eNOS-dependent O(2)(-) production.
J Cardiovasc Pharmacol 2007 Mar
PMID:Pitavastatin restores vascular dysfunction in insulin-resistant state by inhibiting NAD(P)H oxidase activity and uncoupled endothelial nitric oxide synthase-dependent superoxide production. 1741 23


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