NADPH Oxidase

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Karl-heinz Krause - One of the best experts on this subject based on the ideXlab platform.

  • two novel proteins activate superoxide generation by the NADPH Oxidase nox1
    Journal of Biological Chemistry, 2003
    Co-Authors: Botond Banfi, Robert A. Clark, Klaus Steger, Karl-heinz Krause
    Abstract:

    Abstract NOX1, an NADPH Oxidase expressed predominantly in colon epithelium, shows a high degree of similarity to the phagocyte NADPH Oxidase. However, superoxide generation by NOX1 has been difficult to demonstrate. Here we show that NOX1 generates superoxide when co-expressed with the p47phox and p67phox subunits of the phagocyte NADPH Oxidase but not when expressed by itself. Since p47phoxand p67phox are restricted mainly to myeloid cells, we searched for their homologues and identified two novel cDNAs. The mRNAs of both homologues were found predominantly in colon epithelium. Differences between the homologues and the phagocyte NADPH Oxidase subunits included the lack of the autoinhibitory domain and the protein kinase C phosphorylation sites in the p47phox homologue as well as the absence of the first Src homology 3 domain and the presence of a hydrophobic stretch in the p67phox homologue. Co-expression of NOX1 with the two novel proteins led to stimulus-independent high level superoxide generation. Stimulus dependence of NOX1 was restored when p47phox was used to replace its homologue. In conclusion, NOX1 is a superoxide-generating enzyme that is activated by two novel proteins, which we propose to name NOXO1 (NOX organizer 1) and NOXA1 (NOX activator 1).

  • a ca2 activated NADPH Oxidase in testis spleen and lymph nodes
    Journal of Biological Chemistry, 2001
    Co-Authors: Botond Banfi, Klaus Steger, Gergely Molnar, Andres Maturana, Balazs Hegedus, Nicolas Demaurex, Karl-heinz Krause
    Abstract:

    Abstract Superoxide and its derivatives are increasingly implicated in the regulation of physiological functions from oxygen sensing and blood pressure regulation to lymphocyte activation and sperm-oocyte fusion. Here we describe a novel superoxide-generating NADPH Oxidase referred to as NADPH Oxidase 5 (NOX5). NOX5 is distantly related to the gp91phox subunit of the phagocyte NADPH Oxidase with conserved regions crucial for the electron transport (NADPH, FAD and heme binding sites). However, NOX5 has a unique N-terminal extension that contains three EF hand motifs. The mRNA of NOX5 is expressed in pachytene spermatocytes of testis and in B- and T-lymphocyte-rich areas of spleen and lymph nodes. When heterologously expressed, NOX5 was quiescent in unstimulated cells. However, in response to elevations of the cytosolic Ca2+concentration it generated large amounts of superoxide. Upon Ca2+ activation, NOX5 also displayed a second function: it became a proton channel, presumably to compensate charge and pH alterations due to electron export. In summary, we have identified a novel NADPH Oxidase that generates superoxide and functions as a H+ channel in a Ca2+-dependent manner. NOX5 is likely to be involved in Ca2+-activated, redox-dependent processes of spermatozoa and lymphocytes such as sperm-oocyte fusion, cell proliferation, and cytokine secretion.

  • a ca 2 activated NADPH Oxidase in testis spleen and lymph nodes
    Journal of Biological Chemistry, 2001
    Co-Authors: Botond Banfi, Klaus Steger, Gergely Molnar, Andres Maturana, Balazs Hegedus, Nicolas Demaurex, Karl-heinz Krause
    Abstract:

    Abstract Superoxide and its derivatives are increasingly implicated in the regulation of physiological functions from oxygen sensing and blood pressure regulation to lymphocyte activation and sperm-oocyte fusion. Here we describe a novel superoxide-generating NADPH Oxidase referred to as NADPH Oxidase 5 (NOX5). NOX5 is distantly related to the gp91phox subunit of the phagocyte NADPH Oxidase with conserved regions crucial for the electron transport (NADPH, FAD and heme binding sites). However, NOX5 has a unique N-terminal extension that contains three EF hand motifs. The mRNA of NOX5 is expressed in pachytene spermatocytes of testis and in B- and T-lymphocyte-rich areas of spleen and lymph nodes. When heterologously expressed, NOX5 was quiescent in unstimulated cells. However, in response to elevations of the cytosolic Ca2+concentration it generated large amounts of superoxide. Upon Ca2+ activation, NOX5 also displayed a second function: it became a proton channel, presumably to compensate charge and pH alterations due to electron export. In summary, we have identified a novel NADPH Oxidase that generates superoxide and functions as a H+ channel in a Ca2+-dependent manner. NOX5 is likely to be involved in Ca2+-activated, redox-dependent processes of spermatozoa and lymphocytes such as sperm-oocyte fusion, cell proliferation, and cytokine secretion.

Masuko Ushiofukai - One of the best experts on this subject based on the ideXlab platform.

  • reactive oxygen species and angiogenesis NADPH Oxidase as target for cancer therapy
    Cancer Letters, 2008
    Co-Authors: Masuko Ushiofukai, Yoshimasa Nakamura
    Abstract:

    Angiogenesis is essential for tumor growth, metastasis, arteriosclerosis as well as embryonic development and wound healing. Its process is dependent on cell proliferation, migration and capillary tube formation in endothelia cells (ECs). High levels of reactive oxygen species (ROS) such as superoxide and H2O2 are observed in various cancer cells. Accumulating evidence suggests that ROS function as signaling molecules to mediate various growth-related responses including angiogenesis. ROS-dependent angiogenesis can be regulated by endogenous antioxidant enzymes such as SOD and thioredoxin. Vascular endothelial growth factor (VEGF), one of the major angiogenesis factor, is induced in growing tumors and stimulates EC proliferation and migration primarily through the VEGF receptor type2 (VEGFR2, Flk1/KDR). Major source of ROS in ECs is a NADPH Oxidase which consists of Nox1, Nox2, Nox4, Nox5, p22phox, p47phox and the small G protein Rac1. NADPH Oxidase is activated by various growth factors including VEGF and angiopoietin-1 as well as hypoxia and ischemia, and ROS derived from this Oxidase are involved in VEGFR2 autophosphorylation, and diverse redox signaling pathways leading to induction of transcription factors and genes involved in angiogenesis. Dietary antioxidants appear to be effective for treatment of tumor angiogenesis. The aim of this review is to provide an overview of the recent progress on role of ROS derived from NADPH Oxidase and redox signaling events involved in angiogenesis. Understanding these mechanisms may provide insight into the NADPH Oxidase and redox signaling components as potential therapeutic targets for tumor angiogenesis.

  • localizing NADPH Oxidase derived ros
    Science Signaling, 2006
    Co-Authors: Masuko Ushiofukai
    Abstract:

    Reactive oxygen species (ROS) function as signaling molecules to mediate various biological responses, including cell migration, growth, and gene expression. ROS are diffusible and short-lived molecules. Thus, localizing the ROS signal at the specific subcellular compartment is essential for activating redox signaling events after receptor activation. NADPH (nicotinamide adenine dinucleotide phosphate) Oxidase is one of the major sources of ROS in vasculature; it consists of a catalytic subunit (Nox1, Nox2, Nox3, Nox4, or Nox5), p22phox, p47phox, p67phox, and the small guanosine triphosphatase Rac1. Targeting of NADPH Oxidase to focal complexes in lamellipodia and membrane ruffles through the interaction of p47phox with the scaffold proteins TRAF4 and WAVE1 provides a mechanism for achieving localized ROS production, which is required for directed cell migration. ROS are believed to inactivate protein tyrosine phosphatases, which concentrate in specific subcellular compartments, thereby establishing a positive feedback system that activates redox signaling pathways to promote cell movement. Additionally, ROS production may be localized through interactions of NADPH Oxidase with signaling platforms associated with lipid rafts and caveolae, as well as with endosomes. There is also evidence that NADPH Oxidase is found in the nucleus, indicating its involvement in redox-responsive gene expression. This review focuses on targeting of NADPH Oxidase to discrete subcellular compartments as a mechanism of localizing ROS and activation of downstream redox signaling events that mediate various cell functions.

  • redox signaling in angiogenesis role of NADPH Oxidase
    Cardiovascular Research, 2006
    Co-Authors: Masuko Ushiofukai
    Abstract:

    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 H2O2 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.

Botond Banfi - One of the best experts on this subject based on the ideXlab platform.

  • two novel proteins activate superoxide generation by the NADPH Oxidase nox1
    Journal of Biological Chemistry, 2003
    Co-Authors: Botond Banfi, Robert A. Clark, Klaus Steger, Karl-heinz Krause
    Abstract:

    Abstract NOX1, an NADPH Oxidase expressed predominantly in colon epithelium, shows a high degree of similarity to the phagocyte NADPH Oxidase. However, superoxide generation by NOX1 has been difficult to demonstrate. Here we show that NOX1 generates superoxide when co-expressed with the p47phox and p67phox subunits of the phagocyte NADPH Oxidase but not when expressed by itself. Since p47phoxand p67phox are restricted mainly to myeloid cells, we searched for their homologues and identified two novel cDNAs. The mRNAs of both homologues were found predominantly in colon epithelium. Differences between the homologues and the phagocyte NADPH Oxidase subunits included the lack of the autoinhibitory domain and the protein kinase C phosphorylation sites in the p47phox homologue as well as the absence of the first Src homology 3 domain and the presence of a hydrophobic stretch in the p67phox homologue. Co-expression of NOX1 with the two novel proteins led to stimulus-independent high level superoxide generation. Stimulus dependence of NOX1 was restored when p47phox was used to replace its homologue. In conclusion, NOX1 is a superoxide-generating enzyme that is activated by two novel proteins, which we propose to name NOXO1 (NOX organizer 1) and NOXA1 (NOX activator 1).

  • a ca2 activated NADPH Oxidase in testis spleen and lymph nodes
    Journal of Biological Chemistry, 2001
    Co-Authors: Botond Banfi, Klaus Steger, Gergely Molnar, Andres Maturana, Balazs Hegedus, Nicolas Demaurex, Karl-heinz Krause
    Abstract:

    Abstract Superoxide and its derivatives are increasingly implicated in the regulation of physiological functions from oxygen sensing and blood pressure regulation to lymphocyte activation and sperm-oocyte fusion. Here we describe a novel superoxide-generating NADPH Oxidase referred to as NADPH Oxidase 5 (NOX5). NOX5 is distantly related to the gp91phox subunit of the phagocyte NADPH Oxidase with conserved regions crucial for the electron transport (NADPH, FAD and heme binding sites). However, NOX5 has a unique N-terminal extension that contains three EF hand motifs. The mRNA of NOX5 is expressed in pachytene spermatocytes of testis and in B- and T-lymphocyte-rich areas of spleen and lymph nodes. When heterologously expressed, NOX5 was quiescent in unstimulated cells. However, in response to elevations of the cytosolic Ca2+concentration it generated large amounts of superoxide. Upon Ca2+ activation, NOX5 also displayed a second function: it became a proton channel, presumably to compensate charge and pH alterations due to electron export. In summary, we have identified a novel NADPH Oxidase that generates superoxide and functions as a H+ channel in a Ca2+-dependent manner. NOX5 is likely to be involved in Ca2+-activated, redox-dependent processes of spermatozoa and lymphocytes such as sperm-oocyte fusion, cell proliferation, and cytokine secretion.

  • a ca 2 activated NADPH Oxidase in testis spleen and lymph nodes
    Journal of Biological Chemistry, 2001
    Co-Authors: Botond Banfi, Klaus Steger, Gergely Molnar, Andres Maturana, Balazs Hegedus, Nicolas Demaurex, Karl-heinz Krause
    Abstract:

    Abstract Superoxide and its derivatives are increasingly implicated in the regulation of physiological functions from oxygen sensing and blood pressure regulation to lymphocyte activation and sperm-oocyte fusion. Here we describe a novel superoxide-generating NADPH Oxidase referred to as NADPH Oxidase 5 (NOX5). NOX5 is distantly related to the gp91phox subunit of the phagocyte NADPH Oxidase with conserved regions crucial for the electron transport (NADPH, FAD and heme binding sites). However, NOX5 has a unique N-terminal extension that contains three EF hand motifs. The mRNA of NOX5 is expressed in pachytene spermatocytes of testis and in B- and T-lymphocyte-rich areas of spleen and lymph nodes. When heterologously expressed, NOX5 was quiescent in unstimulated cells. However, in response to elevations of the cytosolic Ca2+concentration it generated large amounts of superoxide. Upon Ca2+ activation, NOX5 also displayed a second function: it became a proton channel, presumably to compensate charge and pH alterations due to electron export. In summary, we have identified a novel NADPH Oxidase that generates superoxide and functions as a H+ channel in a Ca2+-dependent manner. NOX5 is likely to be involved in Ca2+-activated, redox-dependent processes of spermatozoa and lymphocytes such as sperm-oocyte fusion, cell proliferation, and cytokine secretion.

Raymond A Swanson - One of the best experts on this subject based on the ideXlab platform.

  • NADPH Oxidase is the primary source of superoxide induced by nmda receptor activation
    Nature Neuroscience, 2009
    Co-Authors: A Brennan, Purnima Narasimhan, Tiina M Kauppinen, Ylva Edling, Pak H Chan, Raymond A Swanson
    Abstract:

    Neuronal NMDA receptor (NMDAR) activation leads to the formation of superoxide, which normally acts in cell signaling. With extensive NMDAR activation, the resulting superoxide production leads to neuronal death. It is widely held that NMDA-induced superoxide production originates from the mitochondria, but definitive evidence for this is lacking. We evaluated the role of the cytoplasmic enzyme NADPH Oxidase in NMDA-induced superoxide production. Neurons in culture and in mouse hippocampus responded to NMDA with a rapid increase in superoxide production, followed by neuronal death. These events were blocked by the NADPH Oxidase inhibitor apocynin and in neurons lacking the p47phox subunit, which is required for NADPH Oxidase assembly. Superoxide production was also blocked by inhibiting the hexose monophosphate shunt, which regenerates the NADPH substrate, and by inhibiting protein kinase C zeta, which activates the NADPH Oxidase complex. These findings identify NADPH Oxidase as the primary source of NMDA-induced superoxide production.

  • hypoglycemic neuronal death is triggered by glucose reperfusion and activation of neuronal NADPH Oxidase
    Journal of Clinical Investigation, 2007
    Co-Authors: Aaron M Hamby, Pak H Chan, Raymond A Swanson
    Abstract:

    Hypoglycemic coma and brain injury are potential complications of insulin therapy. Certain neurons in the hippocampus and cerebral cortex are uniquely vulnerable to hypoglycemic cell death, and oxidative stress is a key event in this cell death process. Here we show that hypoglycemia-induced oxidative stress and neuronal death are attributable primarily to the activation of neuronal NADPH Oxidase during glucose reperfusion. Superoxide production and neuronal death were blocked by the NADPH Oxidase inhibitor apocynin in both cell culture and in vivo models of insulin-induced hypoglycemia. Superoxide production and neuronal death were also blocked in studies using mice or cultured neurons deficient in the p47phox subunit of NADPH Oxidase. Chelation of zinc with calcium disodium EDTA blocked both the assembly of the neuronal NADPH Oxidase complex and superoxide production. Inhibition of the hexose monophosphate shunt, which utilizes glucose to regenerate NADPH, also prevented superoxide formation and neuronal death, suggesting a mechanism linking glucose reperfusion to superoxide formation. Moreover, the degree of superoxide production and neuronal death increased with increasing glucose concentrations during the reperfusion period. These results suggest that high blood glucose concentrations following hypoglycemic coma can initiate neuronal death by a mechanism involving extracellular zinc release and activation of neuronal NADPH Oxidase.

Yoshimasa Nakamura - One of the best experts on this subject based on the ideXlab platform.

  • reactive oxygen species and angiogenesis NADPH Oxidase as target for cancer therapy
    Cancer Letters, 2008
    Co-Authors: Masuko Ushiofukai, Yoshimasa Nakamura
    Abstract:

    Angiogenesis is essential for tumor growth, metastasis, arteriosclerosis as well as embryonic development and wound healing. Its process is dependent on cell proliferation, migration and capillary tube formation in endothelia cells (ECs). High levels of reactive oxygen species (ROS) such as superoxide and H2O2 are observed in various cancer cells. Accumulating evidence suggests that ROS function as signaling molecules to mediate various growth-related responses including angiogenesis. ROS-dependent angiogenesis can be regulated by endogenous antioxidant enzymes such as SOD and thioredoxin. Vascular endothelial growth factor (VEGF), one of the major angiogenesis factor, is induced in growing tumors and stimulates EC proliferation and migration primarily through the VEGF receptor type2 (VEGFR2, Flk1/KDR). Major source of ROS in ECs is a NADPH Oxidase which consists of Nox1, Nox2, Nox4, Nox5, p22phox, p47phox and the small G protein Rac1. NADPH Oxidase is activated by various growth factors including VEGF and angiopoietin-1 as well as hypoxia and ischemia, and ROS derived from this Oxidase are involved in VEGFR2 autophosphorylation, and diverse redox signaling pathways leading to induction of transcription factors and genes involved in angiogenesis. Dietary antioxidants appear to be effective for treatment of tumor angiogenesis. The aim of this review is to provide an overview of the recent progress on role of ROS derived from NADPH Oxidase and redox signaling events involved in angiogenesis. Understanding these mechanisms may provide insight into the NADPH Oxidase and redox signaling components as potential therapeutic targets for tumor angiogenesis.