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

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

  • Biochem Pharmacol. 2019 Oct;168:82-90. doi: 10.1016/j.bcp.2019.06.018.
Shoji Morishige 1,  Fumi Takahashi-Yanaga 2,  Shin Ishikane 3,  Masaki Arioka 4,  Kazunobu Igawa 5,  Akihiro Kuroo 5,  Katsuhiko Tomooka 5,  Akira Shiose 6,  Toshiyuki Sasaguri 7
Affiliations

Affiliations

  • 1 Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan; Department of Cardiovascular Surgery, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
  • 2 Department of Pharmacology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan. Electronic address: ftakahashi@med.uoeh-u.ac.jp.
  • 3 Department of Pharmacology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
  • 4 Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
  • 5 Department of Molecular and Material Science, Institute for Materials Chemistry and Engineering, Kyushu University, Fukuoka, Japan.
  • 6 Department of Cardiovascular Surgery, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
  • 7 Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan. Electronic address: sasaguri@med.kyushu-u.ac.jp.
PMID: 31229551 DOI: 10.1016/j.bcp.2019.06.018
Abstract

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.

Keywords

2,5-Dimethylcelecoxib; Akt; Cardiac fibroblasts; Cardiomyocytes; GSK-3.

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