Background- We previously reported that 2,5-dimethylcelecoxib (DMC) activated glycogen synthase kinase-3 (GSK-3), a negative regulator of cardiac hypertrophy, in mice. In this study, we examined the effects of DMC on isoprenaline (ISO)-induced cardiac hypertrophy and fibrosis using in vivo and in vitro systems.
Methods- ISO (20 mg/kg/day) was administered to C57BL/6J mice using an osmotic pump, and DMC (1,000 ppm) was added into feed for 14 days. Mice were divided into 3 groups: Control, ISO and ISO+DMC. Primary neonatal rat ventricular cardiomyocytes (NRVCs) and adult rat cardiac fibroblasts (RCFs) were pretreated with DMC (3-20 mmol/L) from 1 hour before incubation with ISO (5 mmol/L) for 24 hours. NRVC sizes and RCF proliferation were measured and proteins were examined.
Results- DMC prevented hypertrophy and fibrosis in vivo. DMC attenuated the enlargement of NRVCs by activating GSK-3 and suppressing β-catenin and mTOR. DMC also attenuated RCF proliferation by activating GSK-3 and suppressing cyclin D1. The direct involvement of GSK-3 was verified using a GSK-3 inhibitor SB216763.
Conclusion- DMC prevented cardiac hypertrophy and fibrosis by activating GSK-3 and modulating downstream proteins.