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Title: TNF-{alpha} upregulates the A{sub 2B} adenosine receptor gene: The role of NAD(P)H oxidase 4

Abstract

Proliferation of vascular smooth muscle cells (VSMC), oxidative stress, and elevated inflammatory cytokines are some of the components that contribute to plaque formation in the vasculature. The cytokine tumor necrosis factor-alpha (TNF-{alpha}) is released during vascular injury, and contributes to lesion formation also by affecting VSMC proliferation. Recently, an A{sub 2B} adenosine receptor (A{sub 2B}AR) knockout mouse illustrated that this receptor is a tissue protector, in that it inhibits VSMC proliferation and attenuates the inflammatory response following injury, including the release of TNF-{alpha}. Here, we show a regulatory loop by which TNF-{alpha} upregulates the A{sub 2B}AR in VSMC in vitro and in vivo. The effect of this cytokine is mimicked by its known downstream target, NAD(P)H oxidase 4 (Nox4). Nox4 upregulates the A{sub 2B}AR, and Nox inhibitors dampen the effect of TNF-{alpha}. Hence, our study is the first to show that signaling associated with Nox4 is also able to upregulate the tissue protecting A{sub 2B}AR.

Authors:
; ; ;  [1];  [2]
  1. Department of Biochemistry, Whitaker Cardiovascular Institute, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118 (United States)
  2. Department of Biochemistry, Whitaker Cardiovascular Institute, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118 (United States), E-mail: ravid@biochem.bumc.bu.edu
Publication Date:
OSTI Identifier:
21143906
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 375; Journal Issue: 3; Other Information: DOI: 10.1016/j.bbrc.2008.07.059; PII: S0006-291X(08)01399-5; Copyright (c) 2008 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ADENOSINE; GENE REGULATION; GENES; IN VITRO; IN VIVO; INFLAMMATION; INJURIES; KNOCK-OUT REACTIONS; LYMPHOKINES; MICE; MUSCLES; NAD; OXIDASES; PLAQUE FORMATION; RECEPTORS

Citation Formats

St Hilaire, Cynthia, Koupenova, Milka, Carroll, Shannon H., Smith, Barbara D., and Ravid, Katya. TNF-{alpha} upregulates the A{sub 2B} adenosine receptor gene: The role of NAD(P)H oxidase 4. United States: N. p., 2008. Web. doi:10.1016/j.bbrc.2008.07.059.
St Hilaire, Cynthia, Koupenova, Milka, Carroll, Shannon H., Smith, Barbara D., & Ravid, Katya. TNF-{alpha} upregulates the A{sub 2B} adenosine receptor gene: The role of NAD(P)H oxidase 4. United States. doi:10.1016/j.bbrc.2008.07.059.
St Hilaire, Cynthia, Koupenova, Milka, Carroll, Shannon H., Smith, Barbara D., and Ravid, Katya. 2008. "TNF-{alpha} upregulates the A{sub 2B} adenosine receptor gene: The role of NAD(P)H oxidase 4". United States. doi:10.1016/j.bbrc.2008.07.059.
@article{osti_21143906,
title = {TNF-{alpha} upregulates the A{sub 2B} adenosine receptor gene: The role of NAD(P)H oxidase 4},
author = {St Hilaire, Cynthia and Koupenova, Milka and Carroll, Shannon H. and Smith, Barbara D. and Ravid, Katya},
abstractNote = {Proliferation of vascular smooth muscle cells (VSMC), oxidative stress, and elevated inflammatory cytokines are some of the components that contribute to plaque formation in the vasculature. The cytokine tumor necrosis factor-alpha (TNF-{alpha}) is released during vascular injury, and contributes to lesion formation also by affecting VSMC proliferation. Recently, an A{sub 2B} adenosine receptor (A{sub 2B}AR) knockout mouse illustrated that this receptor is a tissue protector, in that it inhibits VSMC proliferation and attenuates the inflammatory response following injury, including the release of TNF-{alpha}. Here, we show a regulatory loop by which TNF-{alpha} upregulates the A{sub 2B}AR in VSMC in vitro and in vivo. The effect of this cytokine is mimicked by its known downstream target, NAD(P)H oxidase 4 (Nox4). Nox4 upregulates the A{sub 2B}AR, and Nox inhibitors dampen the effect of TNF-{alpha}. Hence, our study is the first to show that signaling associated with Nox4 is also able to upregulate the tissue protecting A{sub 2B}AR.},
doi = {10.1016/j.bbrc.2008.07.059},
journal = {Biochemical and Biophysical Research Communications},
number = 3,
volume = 375,
place = {United States},
year = 2008,
month =
}
  • We demonstrated previously that an {alpha}{sub 1}-{beta}{sub 2}-{gamma}{sub 2} gene cluster of the {gamma}-aminobutyric acid (GABA{sub A}) receptor is located on human chromosome 5q34-q35 and that an ancestral {alpha}-{beta}-{gamma} gene cluster probably spawned clusters on chromosomes 4, 5, and 15. Here, we report that the {alpha}{sub 4} gene (GABRA4) maps to human chromosome 4p14-q12, defining a cluster comprising the {alpha}{sub 2}, {alpha}{sub 4}, {beta}{sub 1}, and {gamma}{sub 1} genes. The existence of an {alpha}{sub 2}-{alpha}{sub 4}-{beta}{sub 1}-{gamma}{sub 2} cluster on chromosome 4 and an {alpha}{sub 1}-{alpha}{sub 6}-{beta}{sub 2}-{gamma}{sub 2} cluster on chromosome 5 provides further evidence that the number ofmore » ancestral GABA{sub A} receptor subunit genes has been expanded by duplication within an ancestral gene cluster. Moreover, if duplication of the {alpha} gene occurred before duplication of the ancestral gene cluster, then a heretofore undiscovered subtype of a subunit should be located on human chromosome 15q11-q13 within an {alpha}{sub 5}-{alpha}{sub x}-{beta}{sub 3}-{gamma}{sub 3} gene cluster at the locus for Angelman and Prader-Willi syndromes. 34 refs., 6 figs., 1 tab.« less
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  • Adenosine modulates important physiologic functions involving the cardiovascular system, brain, kidneys, lungs, GI tract, and immune system. To date four adenosine receptors have been identified: A{sub 1}, A{sub 2a}, A{sub 2b}, and A{sub 3}. Activation of these receptors results in inhibition (A{sub 1} and A{sub 3}) or stimulation (A{sub 2a} and A{sub 2b}) of intracellular adenyl cyclase activity, stimulation of K{sup +} flux, inhibition of Ca{sup 2+} flux, and modulation of inositol phospholipid turnover. A{sub 3} receptors have been identified and sequenced in the testes, brain, lung, liver, kidney, and heart of various species, including the rat, mouse, and human.more » A{sub 3} receptor activation is responsible for release of inflammatory mediators from mast cells, which can cause allergic bronchoconstriction. In addition, they can produce systemic vasodilation and locomotor depression via activation of A{sub 3} receptors in the brain. Given the potential importance of A{sub 3} receptor activity in the pathogenesis of pulmonary, cardiovascular, and central nervous system disease states, we set out to localize the human A{sub 3} adenosine receptor gene (ADORA3). 9 refs., 1 fig.« less
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  • A3 adenosine receptor is a member of Gi protein-coupled receptors that mediate inhibition of adenylate cyclase activity upon binding to the ligand. We determined the chromosome localization of the mouse A3 gene for future genetic studies, utilizing an interspecific backcross panel formed from the cross (C57BL/6J x Mus spretus)F{sub 1} x M. spretus. Genomic DNAs from 94 individuals in the backcross were analyzed by Southern hybridization with murine A3 receptor cDNA probe. Unique map positions were determined by haplotype analysis with 1388 previously mapped loci in the mouse backcross. The mouse A3 receptor gene (Adora3) mapped to chromosome 3, inmore » tight linkage with DNA marker D3Bir15. 12 refs., 1 fig.« less