2,5-Dimethylcelecoxib prevents isoprenaline-induced cardiomyocyte hypertrophy and cardiac fibroblast activation by inhibiting Akt-mediated GSK-3 phosphorylation
| Autor: | Shin Ishikane, Fumi Takahashi-Yanaga, Akira Shiose, Akihiro Kuroo, Kazunobu Igawa, Masaki Arioka, Katsuhiko Tomooka, Shoji Morishige, Toshiyuki Sasaguri |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Male
musculoskeletal diseases 0301 basic medicine Cardiomegaly Left ventricular hypertrophy Biochemistry Rats Sprague-Dawley Glycogen Synthase Kinase 3 Mice 03 medical and health sciences 0302 clinical medicine GSK-3 medicine Animals Tensin PTEN Myocytes Cardiac Phosphorylation Protein kinase B PI3K/AKT/mTOR pathway Pharmacology Sulfonamides Ventricular Remodeling biology Chemistry Isoproterenol Fibroblasts medicine.disease Rats Cell biology Mice Inbred C57BL Disease Models Animal 030104 developmental biology Animals Newborn 030220 oncology & carcinogenesis Heart failure cardiovascular system biology.protein Pyrazoles Proto-Oncogene Proteins c-akt |
| Zdroj: | Biochemical Pharmacology. 168:82-90 |
| ISSN: | 0006-2952 |
| DOI: | 10.1016/j.bcp.2019.06.018 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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