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

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.

• Authors: Shoji Morishige, Fumi Takahashi-Yanaga, Shin Ishikane, Masaki Arioka, Kazunobu Igawa, Akihiro Kuroo, Katsuhiko Tomooka, Akira Shiose, Toshiyuki Sasaguri
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 168 Pg. 82-90 (10 2019) ISSN: 1873-2968 [Electronic] England
• PMID: 31229551 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• 2,5-dimethylcelecoxib
• Pyrazoles
• Sulfonamides
• Proto-Oncogene Proteins c-akt
• Glycogen Synthase Kinase 3
• Isoproterenol

Topics

• Animals
• Animals, Newborn
• Cardiomegaly (chemically induced, drug therapy)
• Disease Models, Animal
• Fibroblasts (drug effects, metabolism)
• Glycogen Synthase Kinase 3 (metabolism)
• Isoproterenol (pharmacology)
• Male
• Mice
• Mice, Inbred C57BL
• Myocytes, Cardiac (drug effects, metabolism)
• Phosphorylation (drug effects)
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors, metabolism)
• Pyrazoles (pharmacology, therapeutic use)
• Rats
• Rats, Sprague-Dawley
• Sulfonamides (pharmacology, therapeutic use)
• Ventricular Remodeling (drug effects)