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Research ArticleCardiovascular

Celecoxib and 2,5-Dimethyl-Celecoxib Prevent Cardiac Remodeling Inhibiting Akt-Mediated Signal Transduction in an Inherited Dilated Cardiomyopathy Mouse Model

Xueli Fan, Fumi Takahashi-Yanaga, Sachio Morimoto, Dong-Yun Zhan, Kazunobu Igawa, Katsuhiko Tomooka and Toshiyuki Sasaguri
Journal of Pharmacology and Experimental Therapeutics July 2011, 338 (1) 2-11; DOI: https://doi.org/10.1124/jpet.111.179325
Xueli Fan
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Fumi Takahashi-Yanaga
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Sachio Morimoto
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Dong-Yun Zhan
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Kazunobu Igawa
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Katsuhiko Tomooka
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Toshiyuki Sasaguri
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Abstract

Celecoxib, a cyclooxygenase-2 (COX-2)-selective nonsteroidal anti-inflammatory drug, has been shown to inhibit Akt and prevent cardiac remodeling in aortic banding-induced failing heart in mice. However, it may be difficult to use celecoxib for the treatment of heart failure because of thromboembolic adverse reactions. Since 2,5-dimethyl (DM)-celecoxib, a derivative unable to inhibit COX-2, has been also reported to inhibit Akt, we attempted to examine whether DM-celecoxib retains the ability to prevent cardiac remodeling and improve cardiac functions using a mouse model of inherited dilated cardiomyopathy (DCM). DM-celecoxib as well as celecoxib administered daily for 4 weeks inhibited Akt and subsequent phosphorylation of glycogen synthase kinase-3β and mammalian target of rapamycin. Furthermore, both celecoxib and DM-celecoxib inhibited the activities of nuclear factor of activated T cell and β-catenin and the expression of TCF7L2 (T-cell-specific transcriptional factor-7L2) and c-Myc, downstream mediators related to cardiac hypertrophy. Functional and morphological measurements showed that these compounds improved left ventricular systolic functions (ejection fraction: vehicle, 34.7 ± 3.9%; 100 mg/kg celecoxib, 50.3 ± 1.1%, p < 0.01; 100 mg/kg DM-celecoxib, 49.8 ± 0.8%, p < 0.01), which was also evidenced by the decrease in β-myosin heavy chain and B-type natriuretic peptide, and prevented hypertrophic cardiac remodeling (heart/body weight ratio: vehicle, 10.4 ± 0.7 mg/g; 100 mg/kg celecoxib, 8.0 ± 0.3 mg/g, p < 0.01; 100 mg/kg DM-celecoxib, 8.2 ± 0.1 mg/g, p < 0.05). As a consequence, both compounds improved the survival rate (vehicle, 45%; 100 mg/kg celecoxib, 75%, p < 0.05; 100 mg/kg DM-celecoxib, 70%, p < 0.05). These results suggested that not only celecoxib but also DM-celecoxib prevents cardiac remodeling and reduces mortality in DCM through a COX-2-independent mechanism involving Akt and its downstream mediators.

Footnotes

  • This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology [Grant 21590284].

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

    doi:10.1124/jpet.111.179325.

  • ABBREVIATIONS:

    DCM
    dilated cardiomyopathy
    LV
    left ventricle
    GSK-3β
    glycogen synthase kinase-3β
    NFAT
    nuclear factor of activated T cell
    COX-2
    cyclooxygenase-2
    DM
    2,5-dimethyl
    mTOR
    mammalian target of rapamycin
    TCF7L2
    T cell-specific transcriptional factor-7L2
    MyHC
    myosin heavy chain
    ANOVA
    analysis of variance
    BNP
    B-type natriuretic peptide
    Dio2
    type 2 iodothyronine deiodinase
    LVEF
    left ventricular ejection fraction
    FS
    fractional shortening
    LVESD
    left ventricular end-systolic diameter
    LVEDD
    left ventricular end-diastolic diameter.

  • Received January 12, 2011.
  • Accepted March 22, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 338 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 338, Issue 1
1 Jul 2011
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Research ArticleCardiovascular

Celecoxib and 2,5-Dimethyl-Celecoxib Prevent Cardiac Remodeling Inhibiting Akt-Mediated Signal Transduction in an Inherited Dilated Cardiomyopathy Mouse Model

Xueli Fan, Fumi Takahashi-Yanaga, Sachio Morimoto, Dong-Yun Zhan, Kazunobu Igawa, Katsuhiko Tomooka and Toshiyuki Sasaguri
Journal of Pharmacology and Experimental Therapeutics July 1, 2011, 338 (1) 2-11; DOI: https://doi.org/10.1124/jpet.111.179325

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Research ArticleCardiovascular

Celecoxib and 2,5-Dimethyl-Celecoxib Prevent Cardiac Remodeling Inhibiting Akt-Mediated Signal Transduction in an Inherited Dilated Cardiomyopathy Mouse Model

Xueli Fan, Fumi Takahashi-Yanaga, Sachio Morimoto, Dong-Yun Zhan, Kazunobu Igawa, Katsuhiko Tomooka and Toshiyuki Sasaguri
Journal of Pharmacology and Experimental Therapeutics July 1, 2011, 338 (1) 2-11; DOI: https://doi.org/10.1124/jpet.111.179325
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