2,5-Dimethylcelecoxib prevents isoprenaline-induced cardiomyocyte hypertrophy and cardiac fibroblast activation by inhibiting Akt-mediated GSK-3 phosphorylation

Shoji Morishige, Fumi Takahashi-Yanaga, Shin Ishikane, Masaki Arioka, Kazunobu Igawa, Akihiro Kuroo, Katsuhiko Tomooka, Akira Shiose, Toshiyuki Sasaguri

研究成果: ジャーナルへの寄稿記事

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We previously reported that 2,5-dimethylcelecoxib (DM-celecoxib), a celecoxib derivative that is unable to inhibit cyclooxygenase-2, prevented cardiac remodeling by activating glycogen synthase kinase-3 (GSK-3) and prolonged the lifespan of heart failure mice with genetic dilated cardiomyopathy or transverse aortic constriction-induced left ventricular hypertrophy. However, it remained unclear how DM-celecoxib regulated structure and function of cardiomyocytes and cardiac fibroblasts involved in cardiac remodeling. In the present study, therefore, we investigated the effect of DM-celecoxib on isoprenaline-induced cardiomyocyte hypertrophy and cardiac fibroblast activation, because DM-celecoxib prevented isoprenaline-induced cardiac remodeling in vivo. DM-celecoxib suppressed isoprenaline-induced neonatal rat cardiomyocyte hypertrophy by the inhibition of Akt phosphorylation resulting in the activation of GSK-3 and the inhibition of β-catenin and mammalian target of rapamycin (mTOR). DM-celecoxib also suppressed the proliferation and the production of matrix metalloproteinase-2 and fibronectin of rat cardiac fibroblasts. Moreover, we found that phosphatase and tensin homolog on chromosome 10 (PTEN) could be a molecule to mediate the effect of DM-celecoxib on Akt. These results suggest that DM-celecoxib directly improves the structure and function of cardiomyocytes and cardiac fibroblasts and that this compound could be clinically useful for the treatment of β-adrenergic receptor-mediated maladaptive cardiac remodeling.

元の言語英語
ページ(範囲)82-90
ページ数9
ジャーナルBiochemical Pharmacology
168
DOI
出版物ステータス出版済み - 10 2019

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All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Pharmacology

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