PT  - JOURNAL ARTICLE
AU  - Xueli Fan
AU  - Fumi Takahashi-Yanaga
AU  - Sachio Morimoto
AU  - Dong-Yun Zhan
AU  - Kazunobu Igawa
AU  - Katsuhiko Tomooka
AU  - Toshiyuki Sasaguri
TI  - Celecoxib and 2,5-Dimethyl-Celecoxib Prevent Cardiac Remodeling Inhibiting Akt-Mediated Signal Transduction in an Inherited Dilated Cardiomyopathy Mouse Model
AID  - 10.1124/jpet.111.179325
DP  - 2011 Jul 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 2--11
VI  - 338
IP  - 1
4099  - http://jpet.aspetjournals.org/content/338/1/2.short
4100  - http://jpet.aspetjournals.org/content/338/1/2.full
SO  - J Pharmacol Exp Ther2011 Jul 01; 338
AB  - Celecoxib, a cyclooxygenase-2 (COX-2)-selective nonsteroidal 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 (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 glycogen synthase kinase-3β and mammalian target of rapamycin. Furthermore, both celecoxib and DM-celecoxib inhibited the activities of nuclear factor of activated T cell and β-catenin and the expression of TCF7L2 (T-cell-specific transcriptional factor-7L2) 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 B-type natriuretic peptide, 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). As a consequence, 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.