Celecoxib, a COX-2-selective non-steroidal anti-inflammatory drug, has been shown to inhibit Akt and prevent cardiac remodeling in aortic banding-induced failing heart in mice. However, it may be difficult to use celecoxib for the treatment of heart failure because of thromboembolic adverse reactions. Since 2,5-dimethyl-celecoxib (DM-celecoxib), a derivative unable to inhibit COX-2, has been also reported to inhibit Akt, we attempted to examine whether DM-celecoxib retains the ability to prevent cardiac remodeling and improve cardiac functions, using a mouse model of inherited dilated cardiomyopathy (DCM). DM-celecoxib as well as celecoxib administered daily for 4 weeks inhibited Akt and subsequent phosphorylation of GSK-3β and mTOR. Further, both celecoxib and DM-celecoxib inhibited the activities of NFAT and β-catenin and the expression of TCF7L2 and c-Myc, downstream mediators related to cardiac hypertrophy. Functional and morphological measurements showed that these compounds improved left ventricular systolic functions (ejection fraction: vehicle, 34.7 ± 3.9%; 100 mg/kg celecoxib, 50.3 ± 1.1%, P<0.01; 100 mg/kg DM-celecoxib, 49.8 ± 0.8%, P<0.01), which was also evidenced by the decrease in β-myosin heavy chain and BNP, and prevented hypertrophic cardiac remodeling (heart/body weight ratio: vehicle, 10.4 ± 0.7 mg/g; 100 mg/kg celecoxib, 8.0 ± 0.3 mg/g, P<0.01; 100 mg/kg DM-celecoxib, 8.2 ± 0.1 mg/g, P<0.05). Consequently, both compounds improved the survival rate (vehicle, 45%; 100 mg/kg celecoxib, 75%, P<0.05; 100 mg/kg DM-celecoxib, 70%, P<0.05). These results suggested that not only celecoxib but also DM-celecoxib prevents cardiac remodeling and reduces mortality in DCM through a COX-2-independent mechanism involving Akt and its downstream mediators.
- Received January 12, 2011.
- Revision received March 9, 2011.
- Accepted March 22, 2011.
- The American Society for Pharmacology and Experimental Therapeutics