Abstract
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.
Footnotes
This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology [Grant 21590284].
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.111.179325.
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ABBREVIATIONS:
- DCM
- dilated cardiomyopathy
- LV
- left ventricle
- GSK-3β
- glycogen synthase kinase-3β
- NFAT
- nuclear factor of activated T cell
- COX-2
- cyclooxygenase-2
- DM
- 2,5-dimethyl
- mTOR
- mammalian target of rapamycin
- TCF7L2
- T cell-specific transcriptional factor-7L2
- MyHC
- myosin heavy chain
- ANOVA
- analysis of variance
- BNP
- B-type natriuretic peptide
- Dio2
- type 2 iodothyronine deiodinase
- LVEF
- left ventricular ejection fraction
- FS
- fractional shortening
- LVESD
- left ventricular end-systolic diameter
- LVEDD
- left ventricular end-diastolic diameter.
- Received January 12, 2011.
- Accepted March 22, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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