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2,5-Dimethylcelecoxib prevents pressure-induced left ventricular remodeling through GSK-3 activation
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2,5-Dimethylcelecoxib prevents pressure-induced left ventricular remodeling through GSK-3 activation
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Journal Article
2,5-Dimethylcelecoxib prevents pressure-induced left ventricular remodeling through GSK-3 activation
2017
Overview
Glycogen synthase kinase-3 (GSK-3) is a crucial regulator of cardiac hypertrophy. We previously reported that 2,5-dimethylcelecoxib (DM-celecoxib), a celecoxib derivative unable to inhibit cyclooxygenase-2, prevented cardiac remodeling by activating GSK-3, resulting in lifespan prolongation in a mouse model of genetic dilated cardiomyopathy. In the present study, we investigated whether DM-celecoxib can also prevent pressure-induced cardiac remodeling and heart failure, elicited by transverse aortic constriction (TAC). Before testing the effects of DM-celecoxib, we compared the effects of TAC on the hearts of wild-type and GSK-3β hetero-deficient (GSK-3β
) mice to determine the role of GSK-3 in cardiac remodeling and heart failure. GSK-3β
mouse hearts exhibited more severe hypertrophy, which was characterized by accelerated interstitial fibrosis, than wild-type mouse hearts after TAC, suggesting that reduced GSK-3β activity aggravates pressure-induced left ventricular remodeling. We subsequently examined the effects of DM-celecoxib on TAC-induced cardiac remodeling. DM-celecoxib inhibited left ventricular systolic functional deterioration, and prevented left ventricular hypertrophy and fibrosis. It also activated GSK-3α and β by inhibiting Akt, suppressing the activity of β-catenin and nuclear factor of activated T-cells and thereby decreasing the expression of the Wnt/β-catenin target gene products fibronectin and matrix metalloproteinase-2. These results suggest that DM-celecoxib is clinically useful for treating pressure-induced heart diseases.
Publisher
Nature Publishing Group
Subject
/ Cardiomyopathy, Dilated - metabolism
/ Cardiomyopathy, Dilated - pathology
/ Glycogen Synthase Kinase 3 - genetics
/ Glycogen Synthase Kinase 3 - metabolism
/ Heart Ventricles - drug effects
/ Heart Ventricles - metabolism
/ Heart Ventricles - pathology
/ Kinases
/ Matrix Metalloproteinase 2 - metabolism
/ Mice
