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.