title: Celecoxib modulates hypertrophic signalling and prevents load-induced cardiac dysfunction.
abstract: In human hearts, the transition from cardiac hypertrophy to advanced heart failure (HF) is accompanied by a tremendous increase in Akt phosphorylation. In non-myocardial tissue, the cyclooxygenase (COX)-2 inhibitor celecoxib has been shown to COX-independently inhibit Akt signalling. We studied the effects of celecoxib on Akt signalling and hypertrophic response in myocardium. In rabbit isolated cardiac myocytes celecoxib concentration-dependently (10-100 micromol/L) inhibited the insulin-induced increase in phosphorylation of Akt and its downstream targets, GSK-3beta and p70 S6 kinase, by reducing the phosphorylation level of the upstream regulator PTEN. Inhibition of Akt signalling was accompanied by a significant suppression of characteristic features of cardiac hypertrophy: Celecoxib concentration-dependently suppressed the agonist-induced enhancement of total protein synthesis and BNP mRNA expression. In mice (C57BL/6NCrl) subjected to left ventricular (LV) pressure overload by aortic banding, celecoxib treatment (50mg x kg-1 x d-1) significantly attenuated LV dilation and contractile dysfunction compared with placebo-treated mice. Moreover, celecoxib significantly reduced mortality 8 weeks after banding. Thus, celecoxib can be used to titrate Akt signalling and hypertrophic response in myocardium. It reduces load-induced LV dilation, contractile dysfunction and mortality in vivo. This may have clinical implications for the prevention and treatment of maladaptive hypertrophy and its progression to HF in humans.
authors.affiliation: Department of Cardiology, University of Göttingen, Göttingen, Germany. jacobshagen@med.uni-goettingen.de
authors.forename: Claudius
authors.initials: C
authors.lastname: Jacobshagen
authors.forename: Meike
authors.initials: M
authors.lastname: Grüber
authors.forename: Nils
authors.initials: N
authors.lastname: Teucher
authors.forename: Albrecht G
authors.initials: AG
authors.lastname: Schmidt
authors.forename: Bernhard W
authors.initials: BW
authors.lastname: Unsöld
authors.forename: Karl
authors.initials: K
authors.lastname: Toischer
authors.forename: Van Phuc
authors.initials: VP
authors.lastname: Nguyen
authors.forename: Lars S
authors.initials: LS
authors.lastname: Maier
authors.forename: Harald
authors.initials: H
authors.lastname: Kögler
authors.forename: Gerd
authors.initials: G
authors.lastname: Hasenfuss
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002311:Cardiomyopathy, Dilated / Q000473:pathology / Q000503:physiopathology*; D002312:Cardiomyopathy, Hypertrophic / Q000473:pathology / Q000503:physiopathology*; D000068579:Celecoxib; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006333:Heart Failure / Q000473:pathology / Q000503:physiopathology*; D007328:Insulin / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009124:Muscle Proteins / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D020097:Natriuretic Peptide, Brain / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000502:physiology; D011720:Pyrazoles / Q000494:pharmacology*; D011817:Rabbits; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013449:Sulfonamides / Q000494:pharmacology*; D018487:Ventricular Dysfunction, Left / Q000473:pathology / Q000503:physiopathology*
chemical_list: D016861:Cyclooxygenase Inhibitors; D007328:Insulin; D009124:Muscle Proteins; D011720:Pyrazoles; D013449:Sulfonamides; D020097:Natriuretic Peptide, Brain; D010656:Phenylephrine; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D038362:Glycogen Synthase Kinase 3; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D000068579:Celecoxib