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  1. Article ; Online: Dynamic regulation of NADPH oxidase 5 by intracellular heme levels and cellular chaperones

    Elizabeth A. Sweeny / Simon Schlanger / Dennis J. Stuehr

    Redox Biology, Vol 36, Iss , Pp 101656- (2020)

    2020  

    Abstract: NADPH oxidase 5 (NOX5) is a transmembrane signaling enzyme that produces superoxide in response to elevated cytosolic calcium. In addition to its association with numerous human diseases, NOX5 has recently been discovered to play crucial roles in the ... ...

    Abstract NADPH oxidase 5 (NOX5) is a transmembrane signaling enzyme that produces superoxide in response to elevated cytosolic calcium. In addition to its association with numerous human diseases, NOX5 has recently been discovered to play crucial roles in the immune response and cardiovascular system. Details of NOX5 maturation, and specifically its response to changes in intracellular heme levels have remained unclear. Here we establish an experimental system in mammalian cells that allows us to probe the influence of heme availability on ROS production by NOX5. We identified a mode of dynamic regulatory control over NOX5 activity through modulation of its heme saturation and oligomeric state by intracellular heme levels and Hsp90 binding. This regulatory mechanism allows for fine-tuning and reversible modulation of NOX5 activity in response to stimuli.
    Keywords NADPH Oxidase ; NOX5 ; Heme ; Hsp90 ; Superoxide ; Medicine (General) ; R5-920 ; Biology (General) ; QH301-705.5
    Language English
    Publishing date 2020-09-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Hemoglobin resident in the lung epithelium is protective for smooth muscle soluble guanylate cyclase function

    Mamta P. Sumi / Blair Tupta / Sanjoy Roychowdhury / Suzy Comhair / Kewal Asosingh / Dennis J. Stuehr / Serpil C. Erzurum / Arnab Ghosh

    Redox Biology, Vol 63, Iss , Pp 102717- (2023)

    2023  

    Abstract: Hemoglobin (Hb) present in the lung epithelium is of unknown significance. However Hb being an nitric oxide (NO) scavenger can bind to NO and reduce its deleterious effects. Hence we postulated an NO scavenging role for this lung Hb. Doing transwell co- ... ...

    Abstract Hemoglobin (Hb) present in the lung epithelium is of unknown significance. However Hb being an nitric oxide (NO) scavenger can bind to NO and reduce its deleterious effects. Hence we postulated an NO scavenging role for this lung Hb. Doing transwell co-culture with bronchial epithelial cells, A549/16-HBE (apical) and human airway smooth muscle cells (HASMCs as basal), we found that Hb can protect the smooth muscle soluble guanylyl cyclase (sGC) from excess NO. Inducing the apical A549/16-HBE cells with cytokines to trigger iNOS expression and NO generation caused a time dependent increase in SNO-sGC and this was accompanied with a concomitant drop in sGC-α1β1 heterodimerization. Silencing Hbαβ in the apical cells further increased the SNO on sGC with a faster drop in the sGC heterodimer and these effects were additive along with further silencing of thioredoxin 1 (Trx1). Since heme of Hb is critical for NO scavenging we determined the Hb heme in a mouse model of allergic asthma (OVA) and found that Hb in the inflammed OVA lungs was low in heme or heme-free relative to those of naïve lungs. Further we established a direct correlation between the status of the sGC heterodimer and the Hb heme from lung samples of human asthma, iPAH, COPD and cystic fibrosis. These findings present a new mechanism of protection of lung sGC by the epithelial Hb, and suggests that this protection maybe lost in asthma or COPD where lung Hb is unable to scavenge the NO due to it being heme-deprived.
    Keywords Inflammation ; Cell Signaling ; Medicine (General) ; R5-920 ; Biology (General) ; QH301-705.5
    Subject code 610
    Language English
    Publishing date 2023-07-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: An inherent dysfunction in soluble guanylyl cyclase is present in the airway of severe asthmatics and is associated with aberrant redox enzyme expression and compromised NO-cGMP signaling

    Arnab Ghosh / Cynthia J. Koziol-White / William F. Jester, Jr. / Serpil C. Erzurum / Kewal Asosingh / Reynold A. Panettieri, Jr. / Dennis J. Stuehr

    Redox Biology, Vol 39, Iss , Pp 101832- (2021)

    2021  

    Abstract: A subset of asthmatics develop a severe form of the disease whose etiology involves airway inflammation along with inherent drivers that remain ill-defined. To address this, we studied human airway smooth muscle cells (HASMC), whose relaxation drives ... ...

    Abstract A subset of asthmatics develop a severe form of the disease whose etiology involves airway inflammation along with inherent drivers that remain ill-defined. To address this, we studied human airway smooth muscle cells (HASMC), whose relaxation drives airway bronchodilation and whose dysfunction contributes to airway obstruction and hypersensitivity in severe asthma. Because HASMC relaxation can be driven by the NO-soluble guanylyl cyclase (sGC)-cGMP signaling pathway, we questioned if HASMC from severe asthma donors might possess inherent defects in their sGC or in redox enzymes that support sGC function. We analyzed HASMC primary lines derived from 17 severe asthma and 16 normal donors and corresponding lung tissue samples regarding sGC activation by NO or by pharmacologic agonists, and also determined expression levels of sGC α1 and β1 subunits, supporting redox enzymes, and related proteins. We found a majority of the severe asthma donor HASMC (12/17) and lung samples primarily expressed a dysfunctional sGC that was NO-unresponsive and had low heterodimer content and high Hsp90 association. This sGC phenotype correlated with lower expression levels of the supporting redox enzymes cytochrome b5 reductase, catalase, and thioredoxin-1, and higher expression of heme oxygenases 1 and 2. Together, our work reveals that severe asthmatics are predisposed toward defective NO-sGC-cGMP signaling in their airway smooth muscle due to an inherent sGC dysfunction, which in turn is associated with inherent changes in the cell redox enzymes that impact sGC maturation and function.
    Keywords Inflammation ; Cell Signaling ; Medicine (General) ; R5-920 ; Biology (General) ; QH301-705.5
    Language English
    Publishing date 2021-02-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Specific O-GlcNAc modification at Ser-615 modulates eNOS function

    Kulwant S. Aulak / Jarrod W. Barnes / Liping Tian / Noel E. Mellor / Mohammad M. Haque / Belinda Willard / Ling Li / Suzy C. Comhair / Dennis J. Stuehr / Raed A. Dweik

    Redox Biology, Vol 36, Iss , Pp 101625- (2020)

    2020  

    Abstract: Idiopathic pulmonary arterial hypertension (IPAH) is a progressive and devastating disease characterized by vascular smooth muscle and endothelial cell proliferation leading to a narrowing of the vessels in the lung. The increased resistance in the lung ... ...

    Abstract Idiopathic pulmonary arterial hypertension (IPAH) is a progressive and devastating disease characterized by vascular smooth muscle and endothelial cell proliferation leading to a narrowing of the vessels in the lung. The increased resistance in the lung and the higher pressures generated result in right heart failure. Nitric Oxide (NO) deficiency is considered a hallmark of IPAH and altered function of endothelial nitric oxide synthase (eNOS), decreases NO production. We recently demonstrated that glucose dysregulation results in augmented protein serine/threonine hydroxyl-linked N-Acetyl-glucosamine (O-GlcNAc) modification in IPAH. In diabetes, dysregulated glucose metabolism has been shown to regulate eNOS function through inhibition of Ser-1177 phosphorylation. However, the link between O-GlcNAc and eNOS function remains unknown. Here we show that increased protein O-GlcNAc occurs on eNOS in PAH and Ser-615 appears to be a novel site of O-GlcNAc modification resulting in reduced eNOS dimerization. Functional characterization of Ser-615 demonstrated the importance of this residue on the regulation of eNOS activity through control of Ser-1177 phosphorylation. Here we demonstrate a previously unidentified regulatory mechanism of eNOS whereby the O-GlcNAc modification of Ser-615 results in reduced eNOS activity and endothelial dysfunction under conditions of glucose dysregulation.
    Keywords Endothelial nitric oxide synthetase ; O-GlcNAc modification ; Pulmonary arterial hypertension ; Nitric oxide ; Medicine (General) ; R5-920 ; Biology (General) ; QH301-705.5
    Subject code 570 ; 610
    Language English
    Publishing date 2020-09-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article: Tetrahydrobiopterin redox cycling in nitric oxide synthase: evidence supports a through‐heme electron delivery

    Ramasamy, Somasundaram / Dennis J. Stuehr / Mahinda Gangoda / Mohammad Mahfuzul Haque

    FEBS journal. 2016 Dec., v. 283, no. 24

    2016  

    Abstract: The nitric oxide synthases (NOS) catalyze a two‐step oxidation of l‐arginine (Arg) to generate NO. In the first step, O₂ activation involves one electron being provided to the heme by an enzyme‐bound 6R‐tetrahydro‐l‐biopterin cofactor (H₄ ... ...

    Abstract The nitric oxide synthases (NOS) catalyze a two‐step oxidation of l‐arginine (Arg) to generate NO. In the first step, O₂ activation involves one electron being provided to the heme by an enzyme‐bound 6R‐tetrahydro‐l‐biopterin cofactor (H₄B), and the H₄B radical must be reduced back to H₄B in order for NOS to continue catalysis. Although an NADPH‐derived electron is used to reduce the H₄B radical, how this occurs is unknown. We hypothesized that the NOS flavoprotein domain might reduce the H₄B radical by utilizing the NOS heme porphyrin as a conduit to deliver the electron. This model predicts that factors influencing NOS heme reduction should also influence the extent and rate of H₄B radical reduction in kind. To test this, we utilized single catalytic turnover and stop‐freeze methods, along with electron paramagnetic resonance spectroscopy, to measure the rate and extent of reduction of the 5‐methyl‐H₄B radical formed in neuronal NOS (nNOS) during Arg hydroxylation. We used several nNOS variants that supported either a slower or faster than normal rate of ferric heme reduction. We found that the rates and extents of nNOS heme reduction correlated well with the rates and extents of 5‐methyl‐H₄B radical reduction among the various nNOS enzymes. This supports a model where the heme porphyrin transfers an electron from the NOS flavoprotein to the H₄B radical formed during catalysis, revealing that the heme plays a dual role in catalyzing O₂ activation or electron transfer at distinct points in the reaction cycle.
    Keywords arginine ; catalytic activity ; electron paramagnetic resonance spectroscopy ; electron transfer ; flavoproteins ; heme ; hydroxylation ; models ; neuronal nitric oxide synthase ; oxidation ; oxygen
    Language English
    Dates of publication 2016-12
    Size p. 4491-4501.
    Publishing place John Wiley & Sons, Ltd
    Document type Article
    Note JOURNAL ARTICLE
    ZDB-ID 2173655-8
    ISSN 1742-4658 ; 1742-464X
    ISSN (online) 1742-4658
    ISSN 1742-464X
    DOI 10.1111/febs.13933
    Database NAL-Catalogue (AGRICOLA)

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  6. Article ; Online: Nitric oxide alters hyaluronan deposition by airway smooth muscle cells.

    Alana K Majors / Ritu Chakravarti / Lisa M Ruple / Rachel Leahy / Dennis J Stuehr / Mark Lauer / Serpil C Erzurum / Allison Janocha / Mark A Aronica

    PLoS ONE, Vol 13, Iss 7, p e

    2018  Volume 0200074

    Abstract: Asthma is a chronic inflammatory disease that is known to cause changes in the extracellular matrix, including changes in hyaluronan (HA) deposition. However, little is known about the factors that modulate its deposition or the potential consequences. ... ...

    Abstract Asthma is a chronic inflammatory disease that is known to cause changes in the extracellular matrix, including changes in hyaluronan (HA) deposition. However, little is known about the factors that modulate its deposition or the potential consequences. Asthmatics with high levels of exhaled nitric oxide (NO) are characterized by greater airway reactivity and greater evidence of airway inflammation. Based on these data and our previous work we hypothesized that excessive NO promotes the pathologic production of HA by airway smooth muscle cells (SMCs). Exposure of cultured SMCs to various NO donors results in the accumulation of HA in the form of unique, cable-like structures. HA accumulates rapidly after exposure to NO and can be seen as early as one hour after NO treatment. The cable-like HA in NO-treated SMC cultures supports the binding of leukocytes. In addition, NO produced by murine macrophages (RAW cells) and airway epithelial cells also induces SMCs to produce HA cables when grown in co-culture. The modulation of HA by NO appears to be independent of soluble guanylate cyclase. Taken together, NO-induced production of leukocyte-binding HA by SMCs provides a new potential mechanism for the non-resolving airway inflammation in asthma and suggests a key role of non-immune cells in driving the chronic inflammation of the submucosa. Modulation of NO, HA and the consequent immune cell interactions may serve as potential therapeutic targets in asthma.
    Keywords Medicine ; R ; Science ; Q
    Subject code 610
    Language English
    Publishing date 2018-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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