2,5-Dimethylcelecoxib attenuates cardiac fibrosis caused by cryoinjury-induced myocardial infarction by suppressing the fibroblast-to-myofibroblast transformation via inhibition of TGF-b signaling pathway

Abstract

We previously reported the 2,5-dimethylcelecoxib (DM-C) attenuated cardiac remodeling in different types of cardiac hypertrophy model. However, it remains unclear whether DM-celecoxib attenuates fibroblast-to-myofibroblast transformation (FMT) which plays the key role in cardiac fibrosis after myocardial infarction (MI). Therefore, we investigated the effect of DM-C on FMT using cryoinjury induced myocardial infarction (CMI) mouse model and TGF-β1-stimulated cardiac fibroblasts. We found that DM-celecoxib attenuated deterioration of left ventricular ejection fraction after CMI by decreasing cardiac fibrosis. Analysis of the expression level of α-smooth muscle actin, a marker for myofibroblast, indicated that DM-celecoxib decreased FMT in cardiac injured site. In the cardiac fibroblasts, DM-celecoxib suppressed expression of α-SMA and phosphorylation levels of Smad 2/3 and GSK-3, indicating that DM-celecoxib suppressed α-SMA expression by inhibiting TGF-β signaling pathway via activation of GSK-3. These results suggested that DM-celecoxib attenuated cardiac fibrosis via suppressing fibroblast-to-myofibroblast transformation in injured site after CMI by suppressing TGF-β signaling pathway via activation of GSK-3. Thus, DM-celecoxib has a potential as a novel anti-fibrotic agent after MI in clinical setting.