| Autor: |
Jacobshagen C; Department of Cardiology, University of Göttingen, Göttingen, Germany. jacobshagen@med.uni-goettingen.de, Grüber M, Teucher N, Schmidt AG, Unsöld BW, Toischer K, Nguyen VP, Maier LS, Kögler H, Hasenfuss G |
| Jazyk: |
angličtina |
| Zdroj: |
European journal of heart failure [Eur J Heart Fail] 2008 Apr; Vol. 10 (4), pp. 334-42. Date of Electronic Publication: 2008 Mar 17. |
| DOI: |
10.1016/j.ejheart.2008.02.013 |
| Abstrakt: |
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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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