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Research ArticleCardiovascular

GS-6201, a Selective Blocker of the A2B Adenosine Receptor, Attenuates Cardiac Remodeling after Acute Myocardial Infarction in the Mouse

Stefano Toldo, Hongyan Zhong, Eleonora Mezzaroma, Benjamin W. Van Tassell, Harsha Kannan, Dewan Zeng, Luiz Belardinelli, Norbert F. Voelkel and Antonio Abbate
Journal of Pharmacology and Experimental Therapeutics December 2012, 343 (3) 587-595; DOI: https://doi.org/10.1124/jpet.111.191288
Stefano Toldo
Virginia Commonwealth University Pauley Heart Center and Victoria Johnson Research Laboratories, Virginia Commonwealth University, Richmond, Virginia (S.T., E.M., B.W.V.T., H.K., N.F.V., A.A.); and Gilead Sciences, Foster City, California (H.Z., D.Z., L.B.)
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Hongyan Zhong
Virginia Commonwealth University Pauley Heart Center and Victoria Johnson Research Laboratories, Virginia Commonwealth University, Richmond, Virginia (S.T., E.M., B.W.V.T., H.K., N.F.V., A.A.); and Gilead Sciences, Foster City, California (H.Z., D.Z., L.B.)
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Eleonora Mezzaroma
Virginia Commonwealth University Pauley Heart Center and Victoria Johnson Research Laboratories, Virginia Commonwealth University, Richmond, Virginia (S.T., E.M., B.W.V.T., H.K., N.F.V., A.A.); and Gilead Sciences, Foster City, California (H.Z., D.Z., L.B.)
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Benjamin W. Van Tassell
Virginia Commonwealth University Pauley Heart Center and Victoria Johnson Research Laboratories, Virginia Commonwealth University, Richmond, Virginia (S.T., E.M., B.W.V.T., H.K., N.F.V., A.A.); and Gilead Sciences, Foster City, California (H.Z., D.Z., L.B.)
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Harsha Kannan
Virginia Commonwealth University Pauley Heart Center and Victoria Johnson Research Laboratories, Virginia Commonwealth University, Richmond, Virginia (S.T., E.M., B.W.V.T., H.K., N.F.V., A.A.); and Gilead Sciences, Foster City, California (H.Z., D.Z., L.B.)
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Dewan Zeng
Virginia Commonwealth University Pauley Heart Center and Victoria Johnson Research Laboratories, Virginia Commonwealth University, Richmond, Virginia (S.T., E.M., B.W.V.T., H.K., N.F.V., A.A.); and Gilead Sciences, Foster City, California (H.Z., D.Z., L.B.)
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Luiz Belardinelli
Virginia Commonwealth University Pauley Heart Center and Victoria Johnson Research Laboratories, Virginia Commonwealth University, Richmond, Virginia (S.T., E.M., B.W.V.T., H.K., N.F.V., A.A.); and Gilead Sciences, Foster City, California (H.Z., D.Z., L.B.)
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Norbert F. Voelkel
Virginia Commonwealth University Pauley Heart Center and Victoria Johnson Research Laboratories, Virginia Commonwealth University, Richmond, Virginia (S.T., E.M., B.W.V.T., H.K., N.F.V., A.A.); and Gilead Sciences, Foster City, California (H.Z., D.Z., L.B.)
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Antonio Abbate
Virginia Commonwealth University Pauley Heart Center and Victoria Johnson Research Laboratories, Virginia Commonwealth University, Richmond, Virginia (S.T., E.M., B.W.V.T., H.K., N.F.V., A.A.); and Gilead Sciences, Foster City, California (H.Z., D.Z., L.B.)
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Abstract

Adenosine (Ado) is released in response to tissue injury, promotes hyperemia, and modulates inflammation. The proinflammatory effects of Ado, which are mediated by the A2B Ado receptor (AdoR), may exacerbate tissue damage. We hypothesized that selective blockade of the A2B AdoR with 3-ethyl-1-propyl-8-(1-(3-trifluoromethylbenzyl)-1H-pyrazol-4-yl)-3,7-dihydropurine-2,6-dione (GS-6201) during acute myocardial infarction (AMI) would reduce adverse cardiac remodeling. Male ICR mice underwent coronary artery ligation or sham surgery (n = 10–12 per group). The selective A2B AdoR antagonist GS-6201 (4 mg/kg) was given intraperitoneally twice daily starting immediately after surgery and continuing for 14 days. Transthoracic echocardiography was performed before surgery and after 7, 14, and 28 days. A subgroup of mice was killed 72 h after surgery, and the activity of caspase-1, a key proinflammatory mediator, was measured in the cardiac tissue. All sham-operated mice were alive at 4 weeks, whereas 50% of vehicle-treated mice and 75% of GS-6201-treated mice were alive at 4 weeks after surgery. Compared with vehicle, treatment with GS-6201 prevented caspase-1 activation in the heart at 72 h after AMI (P < 0.001) and significantly limited the increase in left ventricular (LV) end-diastolic diameter by 40% (P < 0.001), the decrease in LV ejection fraction by 18% (P < 0.01) and the changes in the myocardial performance index by 88% (P < 0.001) at 28 days after AMI. Selective blockade of A2B AdoR with GS-6201 reduces caspase-1 activity in the heart and leads to a more favorable cardiac remodeling after AMI in the mouse.

Footnotes

  • S.T. and H.Z. contributed equally to this work.

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

    http://dx.doi.org/10.1124/jpet.111.191288.

  • ↵Embedded Image The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    AMI
    acute myocardial infarction
    Ado
    adenosine
    AdoR
    Ado receptor
    Ant
    antagonist
    B-mode
    bidimensional mode
    ECL
    enhanced chemiluminescence
    GS-6201
    3-ethyl-1-propyl-8-(1-(3-trifluoromethylbenzyl)-1H-pyrazol-4-yl)-3,7-dihydropurine-2,6-dione
    HR
    heart rate
    ICAM-1
    intercellular adhesion molecule-1
    IL
    interleukin
    LV
    left ventricular
    LVAWDT
    LV anterior wall diastolic thickness
    LVEDD
    LV end diastolic diameter
    LVEF
    LV ejection fraction
    LVESD
    LV end systolic diameter
    LVPSP
    LV peak systolic pressure
    LVPWDT
    LV posterior wall diastolic thickness
    MI
    myocardial infarction
    M-mode
    monodimensional mode
    MPI
    myocardial performance index
    MRS1754
    N-(4-cyanophenyl)-2-(4-(2,3,6,7-tetrahydro-2,6-dioxo-1,3-dipropyl-1H-purin-8-yl)-phenoxy)acetamide
    RV
    right ventricular
    RVEDA
    RV end-diastolic area
    TAPSE
    tricuspid annular plane systolic excursion
    TNF-α
    tumor necrosis factor-α
    VCAM
    vascular cellular adhesion molecule.

  • Received December 26, 2011.
  • Accepted August 23, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 343 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 343, Issue 3
1 Dec 2012
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Research ArticleCardiovascular

Selective A2B Adenosine Receptor Blocker after Acute MI

Stefano Toldo, Hongyan Zhong, Eleonora Mezzaroma, Benjamin W. Van Tassell, Harsha Kannan, Dewan Zeng, Luiz Belardinelli, Norbert F. Voelkel and Antonio Abbate
Journal of Pharmacology and Experimental Therapeutics December 1, 2012, 343 (3) 587-595; DOI: https://doi.org/10.1124/jpet.111.191288

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Research ArticleCardiovascular

Selective A2B Adenosine Receptor Blocker after Acute MI

Stefano Toldo, Hongyan Zhong, Eleonora Mezzaroma, Benjamin W. Van Tassell, Harsha Kannan, Dewan Zeng, Luiz Belardinelli, Norbert F. Voelkel and Antonio Abbate
Journal of Pharmacology and Experimental Therapeutics December 1, 2012, 343 (3) 587-595; DOI: https://doi.org/10.1124/jpet.111.191288
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