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European Journal of Heart Failure 2008 10(4):334-342; doi:10.1016/j.ejheart.2008.02.013
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© 2008 European Society of Cardiology

Celecoxib modulates hypertrophic signalling and prevents load-induced cardiac dysfunction

Claudius Jacobshagena,*, Meike Grübera, Nils Teucherb, Albrecht G. Schmidta, Bernhard W. Unsölda, Karl Toischera, Phuc Nguyen Vana, Lars S. Maiera, Harald Köglera and Gerd Hasenfussa

a Department of Cardiology, University of Göttingen Germany
b Department of Cardiothoracic Surgery, University of Göttingen Germany

* Corresponding author. Department of Cardiology Georg-August-University Robert-Koch-Strasse 40 D-37075 Göttingen, Germany. Tel.: +49 551 39 6380; fax: +49 551 39 2953. E-mial address: jacobshagen{at}med.uni-goettingen.de (C. Jacobshagen).


  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 µmol/L) inhibited the insulin-induced increase in phosphorylation of Akt and its downstream targets, GSK-3β 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.

Key Words: Hypertrophy • Heart failure • Celecoxib • Akt signalling • Aortic banding

Received July 17, 2007; Revised November 30, 2007; Accepted February 19, 2008


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