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Research ArticleCardiovascular

NADPH Oxidase Pathway Is Involved in Aortic Contraction Induced by A3 Adenosine Receptor in Mice

Mohammed S. El-Awady, Habib R. Ansari, Daniel Fil, Stephen L. Tilley and S. Jamal Mustafa
Journal of Pharmacology and Experimental Therapeutics August 2011, 338 (2) 711-717; DOI: https://doi.org/10.1124/jpet.111.180828
Mohammed S. El-Awady
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Habib R. Ansari
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Daniel Fil
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Stephen L. Tilley
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S. Jamal Mustafa
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Abstract

The NADPH oxidase (Nox) subunits 1, 2 (gp91 phox), and 4 are the major sources for reactive oxygen species (ROS) in vascular tissues. In conditions such as ischemia-reperfusion and hypoxia, both ROS and adenosine are released, suggesting a possible interaction. Our aim in this study was to examine the A3 adenosine receptor (A3AR)-induced vascular effects and its relation to ROS and Nox1, 2, and 4 using aortic tissues from wild-type (WT) and A3AR knockout (A3KO) mice. The selective A3AR agonist 2-chloro-N6-(3-iodobenzyl)-adenosine-5′-N-methyluronamide (Cl-IBMECA) (10−10–10−5 M) induced contraction of the aorta from WT but not from A3KO mice, and this contraction was inhibited by the Nox inhibitor apocynin (10−5 M) and the ROS scavengers superoxide dismutase-polyethylene glycol and catalase-polyethylene glycol (100 U/ml each). Cl-IBMECA-induced contraction was not affected by the mast cell degranulator compound 48/80 (100 μg/ml) or the stabilizer cromolyn sodium (10−4 M). In addition, Cl-IBMECA (10−7 M) increased intracellular ROS generation by 35 ± 14% in WT but not in A3KO aorta, and this increase was inhibited by apocynin (10−5 M), diphenyleneiodonium chloride (10−5 M), and the A3AR antagonist 3-propyl-6-ethyl-5-[(ethylthio)carbonyl]-2 phenyl-4-propyl-3-pyridine carboxylate (MRS1523) (10−5 M). Furthermore, Cl-IBMECA selectively increased the protein expression of the Nox2 subunit by 150 ± 15% in WT but not in A3KO mice without affecting either Nox1 or 4, and this increase was inhibited by apocynin. The mRNA of Nox2 was unchanged by Cl-IBMECA in either WT or A3KO aortas. In conclusion, A3AR enhances ROS generation, possibly through activation of Nox2, with subsequent contraction of the mouse aorta.

Footnotes

  • This study was supported by National Institutes of Health National Heart, Lung, and Blood Institute [Grants HL027339, HL094447, HL071802].

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    doi:10.1124/jpet.111.180828.

  • ABBREVIATIONS:

    AR
    adenosine receptor
    COX-1
    cyclooxygenase-1
    KO
    knockout
    Nox
    NADPH oxidase(s)
    ROS
    reactive oxygen species
    Cl-IBMECA
    2-chloro-N6-(3-iodobenzyl)-adenosine-5′-N-methyluronamide
    WT
    wild type
    A3KO
    A3AR knockout
    KH buffer
    Krebs-Henseleit buffer
    PE
    phenylephrine
    DPI
    diphenyleneiodonium chloride
    MRS1523
    3-propyl-6-ethyl-5-[(ethylthio)carbonyl]-2 phenyl-4-propyl-3-pyridine carboxylate
    PEG-SOD
    superoxide dismutase-polyethylene glycol
    PEG-catalase
    catalase-polyethylene glycol
    DCFH-DA
    2′,7′-dichlorofluorescin diacetate
    DCF
    2′,7′-dichlorofluorescin
    ANOVA
    analysis of variance.

  • Received February 18, 2011.
  • Accepted May 20, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 338 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 338, Issue 2
1 Aug 2011
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Research ArticleCardiovascular

NADPH Oxidase Pathway Is Involved in Aortic Contraction Induced by A3 Adenosine Receptor in Mice

Mohammed S. El-Awady, Habib R. Ansari, Daniel Fil, Stephen L. Tilley and S. Jamal Mustafa
Journal of Pharmacology and Experimental Therapeutics August 1, 2011, 338 (2) 711-717; DOI: https://doi.org/10.1124/jpet.111.180828

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Research ArticleCardiovascular

NADPH Oxidase Pathway Is Involved in Aortic Contraction Induced by A3 Adenosine Receptor in Mice

Mohammed S. El-Awady, Habib R. Ansari, Daniel Fil, Stephen L. Tilley and S. Jamal Mustafa
Journal of Pharmacology and Experimental Therapeutics August 1, 2011, 338 (2) 711-717; DOI: https://doi.org/10.1124/jpet.111.180828
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