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

We previously reported that 2,5-dimethylcelecoxib (DM-C), a derivative of celecoxib, lacks cyclooxygenase-2 inhibitory effects and suppresses cardiac remodeling by activating glycogen synthase kinase-3 (GSK-3). How -ever, it remains unclear whether DM-C attenuates fibroblast-to-myofibroblast transformation (FMT), which plays a key role in cardiac fibrosis. Therefore, we evaluated the effect of DM-C on FMT using a cryoinjury-induced myocardial infarction (CMI) mouse model. We found that DM-C attenuated the deterioration of left ventricu-lar ejection fraction after CMI by decreasing cardiac fibrosis. Analysis of the expression level of alpha-smooth muscle actin (alpha-SMA), a marker for myofibroblasts, indicated that DM-C decreased FMT at the cardiac injury site. To investigate the mechanism by which DM-C attenuated FMT, fibroblasts obtained from the heart were stimulated with TGF-beta to induce FMT, and the effect of DM-C was analyzed. DM-C suppressed the expression of alpha-SMA and the phosphorylation levels of Smad 2/3 and GSK-3, indicating that DM-C suppressed alpha-SMA expression by inhibiting the transforming growth factor (TGF)-beta signaling pathway via activation of GSK-3. DM-C decreased the expression of collagen, connective tissue growth factor (CTGF) and Snail, which are also known to accelerate cardiac fibrosis. These results suggested that DM-C attenuated cardiac fibrosis by suppressing FMT at the injured site after CMI by inhibiting the TGF-beta signaling pathway via activation of GSK-3. Thus, DM-C has potential against cardiac disease as a novel anti-fibrotic agent.

Automated summary

2,5-dimethylcelecoxib (DM-C) attenuates fibroblast-to-myofibroblast transformation (FMT) and decreases cardiac fibrosis by inhibiting the TGF-beta signaling pathway through activation of GSK-3.