Celecoxib modulates hypertrophic signalling and prevents load-induced cardiac dysfunction
2008 | journal article; research paper. A publication with affiliation to the University of Göttingen.
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Celecoxib modulates hypertrophic signalling and prevents load-induced cardiac dysfunction
Jacobshagen, C. ; Grueber, M.; Teucher, N. ; Schmidt, A. G.; Unsoeld, B. W.; Toischer, K. & Van, P. N. et al. (2008)
European Journal of Heart Failure, 10(4) pp. 334-342. DOI: https://doi.org/10.1016/j.ejheart.2008.02.013
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- Authors
- Jacobshagen, Claudius ; Grueber, Meike; Teucher, Nils ; Schmidt, Albrecht G.; Unsoeld, Bernhard W.; Toischer, Karl ; Van, Phuc Nguyen; Maier, Lars S. ; Koegler, Harald; Hasenfuß, Gerd
- 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 mu mol/L) inhibited the insulin-induced increase in phosphorylation of Akt and its downstream targets, GSK-3 beta 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 (50 mg.kg(-1).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. (C) 2008 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
- Issue Date
- 2008
- Publisher
- Elsevier Science Bv
- Journal
- European Journal of Heart Failure
- ISSN
- 1388-9842