title: Celecoxib and 2,5-dimethyl-celecoxib prevent cardiac remodeling inhibiting Akt-mediated signal transduction in an inherited dilated cardiomyopathy mouse model.
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.
authors.affiliation: Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Xueli
authors.initials: X
authors.lastname: Fan
authors.forename: Fumi
authors.initials: F
authors.lastname: Takahashi-Yanaga
authors.forename: Sachio
authors.initials: S
authors.lastname: Morimoto
authors.forename: Dong-Yun
authors.initials: DY
authors.lastname: Zhan
authors.forename: Kazunobu
authors.initials: K
authors.lastname: Igawa
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Tomooka
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sasaguri
mesh_terms: D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D000068579:Celecoxib; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D055879:Gene Knock-In Techniques; D051379:Mice; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000502:physiology; D011720:Pyrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D020257:Ventricular Remodeling / Q000187:drug effects* / Q000235:genetics
chemical_list: C506698:2,5-dimethylcelecoxib; D011720:Pyrazoles; D013449:Sulfonamides; D051057:Proto-Oncogene Proteins c-akt; D000068579:Celecoxib