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)

Vascular endothelial growth factor (VEGF) is a potent vascular endothelial cell-specific mitogen that modulates endothelial cell function. In the present study, we show that VEGF induces manganese-superoxide dismutase (MnSOD) mRNA and protein in human coronary artery endothelial cells (HCAEC) and pulmonary artery endothelial cells. VEGF-mediated induction of MnSOD mRNA was inhibited by pretreatment with the NADPH oxidase inhibitors, diphenyleneiodonium (DPI), and 4-(2-aminoethyl)-benzenesulfonyl fluoride, but not with the nitric oxide synthase inhibitor L-NAME (N-monomethyl-L-arginine) or the xanthine oxidase inhibitor allopurinol. VEGF stimulation of MnSOD was also inhibited by adenoviral-mediated overexpression of catalase Cu, Zn-SOD and a dominant-negative form of the small GTPase component of NADPH oxidase Rac1 (Rac1N17). Treatment of HCAEC with VEGF resulted in a transient increase in ROS production at 20 min, as measured by 2,7-dichlorodihydrofluorescein oxidation. This effect was abrogated by expression of Rac1N17. Taken together, these findings suggest that VEGF induces MnSOD by an NADPH oxidase-dependent mechanism and that VEGF signaling in the endothelium is coupled to the redox state of the cell.
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PMID:Vascular endothelial growth factor induces manganese-superoxide dismutase expression in endothelial cells by a Rac1-regulated NADPH oxidase-dependent mechanism. 1164 Dec 65

Vascular endothelial growth factor (VEGF) induces angiogenesis by stimulating endothelial cell proliferation and migration, primarily through the receptor tyrosine kinase VEGF receptor2 (Flk1/KDR). Reactive oxygen species (ROS) derived from NAD(P)H oxidase are critically important in many aspects of vascular cell regulation, and both the small GTPase Rac1 and gp91(phox) are critical components of the endothelial NAD(P)H oxidase complex. A role of NAD(P)H oxidase in VEGF-induced angiogenesis, however, has not been defined. In the present study, electron spin resonance spectroscopy is utilized to demonstrate that VEGF stimulates O2*- production, which is inhibited by the NAD(P)H oxidase inhibitor, diphenylene iodonium, as well as by overexpression of dominant-negative Rac1 (N17Rac1) and transfection of gp91(phox) antisense oligonucleotides in human umbilical vein endothelial cells (ECs). Antioxidants, including N-acetylcysteine (NAC), various NAD(P)H oxidase inhibitors, and N17Rac1 significantly attenuate not only VEGF-induced KDR tyrosine phosphorylation but also proliferation and migration of ECs. Importantly, these effects of VEGF are dramatically inhibited in cells transfected with gp91(phox) antisense oligonucleotides. By contrast, ROS are not involved in mediating these effects of sphingosine 1-phosphate (S1P) on ECs. Sponge implant assays demonstrate that VEGF-, but not S1P-, induced angiogenesis is significantly reduced in wild-type mice treated with NAC and in gp91(phox-/-) mice, suggesting that ROS derived from gp91(phox)-containing NAD(P)H oxidase play an important role in angiogenesis in vivo. These studies indicate that VEGF-induced endothelial cell signaling and angiogenesis is tightly controlled by the reduction/oxidation environment at the level of VEGF receptor and provide novel insights into the NAD(P)H oxidase as a potential therapeutic target for angiogenesis-dependent diseases.
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PMID:Novel role of gp91(phox)-containing NAD(P)H oxidase in vascular endothelial growth factor-induced signaling and angiogenesis. 2436 30

Vascular endothelial growth factor (VEGF) released by osteoblasts plays an important role in angiogenesis and endochondral ossification during bone formation. In animal studies, we have reported that shock waves (SW) can promote osteogenic differentiation of mesenchymal stem cells through superoxide-mediated signal transduction (Wang, F. S., Wang, C. J., Sheen-Chen, S. M., Kuo, Y. R., Chen, R. F., and Yang, K. D. (2002) J. Biol. Chem. 277, 10931-10937) and vascularization of the bone-tendon junction. Here, we found that SW elevation of VEGF-A expression in human osteoblasts to be mediated by Ras-induced superoxide and ERK-dependent HIF-1alpha activation. SW treatment (0.16 mJ/mm(2), 1 Hz, 500 impulses) rapidly activated Ras protein (15 min) and Rac1 protein (30 min) and increased superoxide production in 30 min and VEGF mRNA expression in 6 h. Early scavenging of superoxide, but not nitric oxide, peroxide hydrogen, or prostaglandin E(2), reduced SW-augmented VEGF-A levels. Inhibition of superoxide production by diphenyliodonium, an NADPH oxidase inhibitor, was found to suppress VEGF-A expression. Transfection of osteoblasts with a dominant negative (S17N) Ras mutant abrogated the SW enhancement of Rac1 activation, superoxide synthesis, and VEGF expression. Further studies demonstrated that SW significantly promoted ERK activation in 1 h and HIF-1alpha phosphorylation and HIF-1alpha binding to VEGF promoter in 3 h. In support of the observation that superoxide mediated the SW-induced ERK activation and HIF-1alpha transactivation, we further demonstrated that scavenging of superoxide by superoxide dismutase and inhibition of ERK activity by PD98059 decreased HIF-1alpha activation and VEGF-A levels. Moreover, culture medium harvested from SW-treated osteoblasts increased vessel number of chick chorioallantoic membrane. Superoxide dismutase pretreatment and anti-VEGF-A antibody neutralization reduced the promoting effect of conditioned medium on angiogenesis. Thus, modulation of redox reaction by SW may have some positive effect on angiogenesis during bone regeneration.
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PMID:Ras induction of superoxide activates ERK-dependent angiogenic transcription factor HIF-1alpha and VEGF-A expression in shock wave-stimulated osteoblasts. 1468 Dec 37

The mitochondrial antioxidant manganese superoxide dismutase (Mn-SOD) plays a critical cytoprotective role against oxidative stress. Vascular endothelial growth factor (VEGF) was shown previously to induce expression of Mn-SOD in endothelial cells by a NADPH oxidase-dependent mechanism. The goal of the current study was to determine the transcriptional mechanisms underlying this phenomenon. VEGF resulted in protein kinase C-dependent phosphorylation of IkappaB and subsequent translocation of p65 NF-kappaB into the nucleus. Overexpression of constitutively active IkappaB blocked VEGF stimulation of Mn-SOD. In transient transfection assays, VEGF increased Mn-SOD promoter activity, an effect that was dependent on a second intronic NF-kappaB consensus motif. In contrast, VEGF-mediated induction of Mn-SOD was enhanced by the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 and by dominant negative Akt and was decreased by constitutively active Akt. Overexpression of a constitutively active (phosphorylation-resistant) form of FKHRL1 (TMFKHRL1) resulted in increased Mn-SOD expression, suggesting that the negative effect of PI3K-Akt involves attenuation of forkhead activity. In co-transfection assays, the Mn-SOD promoter was transactivated by TMFKHRL1. Flavoenzyme inhibitor, diphenyleneiodonium (DPI), and antisense oligonucleotides against p47phox (AS-p47phox) inhibited VEGF stimulation of IkappaB/NF-kappaB and forkhead phosphorylation, supporting a role for NADPH oxidase activity in both signaling pathways. Like VEGF, hepatocyte growth factor (HGF) activated the PI3K-Akt-forkhead pathway. However, HGF-PI3K-Akt-forkhead signaling was insensitive to diphenyleneiodonium and AS-p47phox. Moreover, HGF failed to induce phosphorylation of IkappaB/NF-kappaB or nuclear translocation of NF-kappaB and had no effect on Mn-SOD expression. Together, these data suggest that VEGF is uniquely coupled to Mn-SOD expression through growth factor-specific reactive oxygen species (ROS)-sensitive positive (protein kinase C-NF-kappaB) and negative (PI3K-Akt-forkhead) signaling pathways.
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PMID:Vascular endothelial growth factor-mediated induction of manganese superoxide dismutase occurs through redox-dependent regulation of forkhead and IkappaB/NF-kappaB. 1530 28

Angiogenesis, a process of new blood vessel growth, contributes to various pathophysiologies such as cancer, diabetic retinopathy and atherosclerosis. Accumulating evidence suggests that cardiovascular diseases are associated with increased oxidative stress in blood vessels. Reactive oxygen species (ROS) such as superoxide and H2O2 cause blood vessels to thicken, produce inflammation in the vessel wall, and thus are regarded as "risk factors" for vascular disease, whereas ROS also act as signaling molecules in many aspects of growth factor-mediated physiological responses. Recent reports suggest that ROS play an important role in angiogenesis; however, its underlying molecular mechanisms remain unknown. Vascular endothelial growth factor (VEGF) induces angiogenesis by stimulating endothelial cell (EC) proliferation and migration primarily through the receptor tyrosine kinase VEGF receptor2 (Flk1/KDR). VEGF binding initiates tyrosine phosphorylation of KDR, which results in activation of downstream signaling enzymes including ERK1/2, Akt and eNOS, which contribute to angiogenic-related responses in EC. Importantly, the major source of ROS in EC is a NAD(P)H oxidase and EC express all the components of phagocytic NAD(P)H oxidase including gp91phox, p22phox, p47phox, p67phox and the small G protein Rac1. We have recently demonstrated that ROS derived from NAD(P)H oxidase are critically important for VEGF signaling in vitro and angiogenesis in vivo. Furthermore, a peptide hormone, angiotensin II, a major stimulus for vascular NAD(P)H oxidase, also plays an important role in angiogenesis. Because EC migration and proliferation are primary features of the process of myocardial angiogenesis, we would like to focus on the recent progress that has been made in the emerging area of NAD(P)H oxidase-derived ROS-dependent signaling in ECs, and discuss the possible roles in angiogenesis. Understanding these mechanisms may provide insight into the components of NAD(P)H oxidase as potential therapeutic targets for treatment of angiogenesis-dependent diseases such as cancer and atherosclerosis and for promoting myocardial angiogenesis in ischemic heart diseases.
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PMID:Reactive oxygen species as mediators of angiogenesis signaling: role of NAD(P)H oxidase. 1554 38

Angiogenesis, a process by which new vascular networks are formed from pre-existing capillaries, is required for tumors to grow, invade, and metastasize. Vascular endothelial growth factor (VEGF), a specific mitogen to endothelial cells, is a crucial factor for tumor angiogenesis. In this study, we investigated whether minodronate, a newly developed nitrogen-containing bisphosphonate, could inhibit melanoma growth and improve survival in nude mice by suppressing the VEGF signaling. We found here that minodronate inhibited melanoma growth and improved survival in nude mice by suppressing the tumor-associated angiogenesis and macrophage infiltration. Minodronate completely inhibited the VEGF-induced increase in DNA synthesis and tube formation in endothelial cells by suppressing NADPH oxidase-mediated reactive oxygen species generation and Ras activation. Furthermore, minodronate inhibited the VEGF-induced expression of intercellular adhesion molecule-1 and monocyte chemoattractant protein-1 in endothelial cells. Minodronate decreased DNA synthesis and increased apoptotic cell death of cultured melanoma cells as well. Our present study suggests that minodronate might suppress melanoma growth and improve survival in nude mice by two independent mechanisms; one is by blocking the VEGF signaling in endothelial cells, and the other is by inducing apoptotic cell death of melanoma. The present study provides a novel potential therapeutic strategy for the treatment of melanoma.
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PMID:Minodronate, a newly developed nitrogen-containing bisphosphonate, suppresses melanoma growth and improves survival in nude mice by blocking vascular endothelial growth factor signaling. 1557 31

Vascular endothelial growth factor (VEGF) stimulates endothelial cell (EC) migration and proliferation primarily through the VEGF receptor-2 (VEGFR2). We have shown that VEGF stimulates a Rac1-dependent NAD(P)H oxidase to produce reactive oxygen species (ROS) that are involved in VEGFR2 autophosphorylation and angiogenic-related responses in ECs. The small GTPase ARF6 is involved in membrane trafficking and cell motility; however, its roles in VEGF signaling and physiological responses in ECs are unknown. In this study, we show that overexpression of dominant-negative ARF6 [ARF6(T27N)] almost completely inhibits VEGF-induced Rac1 activation, ROS production, and VEGFR2 autophosphorylation in ECs. Fractionation of caveolae/lipid raft membranes demonstrates that ARF6, Rac1, and VEGFR2 are localized in caveolin-enriched fractions basally. VEGF stimulation results in the release of VEGFR2 from caveolae/lipid rafts and caveolin-1 without affecting localization of ARF6, Rac1, or caveolin-1 in these fractions. The egress of VEGFR2 from caveolae/lipid rafts is contemporaneous with the tyrosine phosphorylation of caveolin-1 (Tyr14) and VEGFR2 and with their association with each other. ARF6(T27N) significantly inhibits both VEGF-induced responses. Immunofluorescence studies show that activated VEGFR2 and phosphocaveolin colocalize at focal complexes/adhesions after VEGF stimulation. Both overexpression of ARF6(T27N) and mutant caveolin-1(Y14F), which cannot be phosphorylated, block VEGF-stimulated EC migration and proliferation. Moreover, ARF6 expression is markedly upregulated in association with an increase in capillary density in a mouse hindlimb ischemia model of angiogenesis. Thus, ARF6 is involved in the temporal-spatial organization of caveolae/lipid rafts- and ROS-dependent VEGF signaling in ECs as well as in angiogenesis in vivo.
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PMID:Novel role of ARF6 in vascular endothelial growth factor-induced signaling and angiogenesis. 1569 85

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.
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PMID:Redox signaling in angiogenesis: role of NADPH oxidase. 1678 92

Vascular endothelial growth factor (VEGF) is the most potent stimulatory factor of angiogenesis. Its expression is induced by reactive oxygen species (ROS) in hypoxic conditions and by insulin in normoxic cells. Both ROS and insulin can activate mitogen-activated protein kinases (MAPKs) and induce the transcriptional factor Sp1, components that are essential for VEGF gene expression. The aim of this study was to investigate the role of ROS producing NADPH oxidase enzymes (NOX-es) in insulin-regulated VEGF gene activation. To achieve this goal we chose HepG2 cells as our model system as these cells express the NADPH oxidase isoform NOX3 and respond to insulin stimulation with enhanced ROS production and mRNA transcription and production of VEGF. We demonstrate that in control cells insulin stimulation leads to H2O2 generation, a biphasic activation of p42/44 MAPK and the induction of both Sp1 and HIF-1alpha. Transfection of NOX3-specific siRNA abrogates H2O2 production and inhibits exclusively the second phase of p42/44 MAPK phosphorylation and Sp1 DNA binding and thus prevents upregulation of VEGF-A mRNA expression. In conclusion, our results demonstrate that NOX3, a ROS generating NADPH oxidase, plays an integral role in insulin-induced p42/44 MAPK signal transmission and VEGF-A production.
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PMID:Insulin-induced vascular endothelial growth factor expression is mediated by the NADPH oxidase NOX3. 1694 73

Angiogenesis is a key process involved in normal development and wound repair, as well as ischemic heart and limb diseases, and atherosclerosis. Vascular endothelial growth factor (VEGF), a potent angiogenesis factor, stimulates proliferation, migration, and tube formation of endothelial cells (ECs), primarily through the VEGF receptor type2 (VEGFR2). Reactive oxygen species (ROS) function as signaling molecules to mediate biological responses. In ECs, NADPH oxidase is one of the major sources of ROS and consists of catalytic subunits (Nox1, Nox2, and Nox4), p22phox, p47phox, p67phox, and the small GTPase Rac1. VEGF stimulates ROS production via activation of gp91phox (Nox2)-based NADPH oxidase, and ROS are involved in VEGFR2-mediated signaling linked to EC migration and proliferation. Moreover, ROS derived from NADPH oxidase are involved in postnatal angiogenesis. Localizing NADPH oxidase and its regulators at the specific subcellular compartment is an important mechanism for activating specific redox signaling events. This review focuses on a role of NADPH oxidase-derived ROS in angiogenesis and critical regulators involved in generation of spatially and temporally restricted ROS-dependent VEGF signaling at leading edge, focal adhesions/complexes, caveolae/lipid rafts, and cell-cell junctions in ECs. Understanding these mechanisms should facilitate the development of new therapeutic strategies to modulate new blood vessel formation.
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PMID:VEGF signaling through NADPH oxidase-derived ROS. 1751 88


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