Celecoxib modulates hypertrophic signalling and prevents load-induced cardiac dysfunction.
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.
Jacobshagen
Claudius
C
Department of Cardiology, University of Göttingen, Göttingen, Germany. jacobshagen@med.uni-goettingen.de
Grüber
Meike
M
Teucher
Nils
N
Schmidt
Albrecht G
AG
Unsöld
Bernhard W
BW
Toischer
Karl
K
Nguyen
Van Phuc
VP
Maier
Lars S
LS
Kögler
Harald
H
Hasenfuss
Gerd
G
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*
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