title: 2,5-Dimethylcelecoxib prevents pressure-induced left ventricular remodeling through GSK-3 activation.
abstract: 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.
authors.affiliation: Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.|Department of Anesthesia and Critical Care Medicine, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Ai
authors.initials: A
authors.lastname: Fujita
authors.affiliation: Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.|Global Medical Science Education Unit, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Fumi
authors.initials: F
authors.lastname: Takahashi-Yanaga
authors.affiliation: Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Sachio
authors.initials: S
authors.lastname: Morimoto
authors.affiliation: Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Yoshihara
authors.affiliation: Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Arioka
authors.affiliation: Department of Molecular and Material Science, Institute for Materials Chemistry and Engineering, Kyushu University, Fukuoka, Japan.
authors.forename: Kazunobu
authors.initials: K
authors.lastname: Igawa
authors.affiliation: Department of Molecular and Material Science, Institute for Materials Chemistry and Engineering, Kyushu University, Fukuoka, Japan.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Tomooka
authors.affiliation: Department of Anesthesia and Critical Care Medicine, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Sumio
authors.initials: S
authors.lastname: Hoka
authors.affiliation: Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sasaguri
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000378:metabolism* / Q000473:pathology; D002311:Cardiomyopathy, Dilated / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D006352:Heart Ventricles / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: C506698:2,5-dimethylcelecoxib; D011720:Pyrazoles; D013449:Sulfonamides; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D020778:Matrix Metalloproteinase 2