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Celecoxib modulates hypertrophic signalling and prevents load‐induced cardiac dysfunction
Author(s) -
Jacobshagen Claudius,
Grüber Meike,
Teucher Nils,
Schmidt Albrecht G.,
Unsöld Bernhard W.,
Toischer Karl,
Nguyen Van Phuc,
Maier Lars S.,
Kögler Harald,
Hasenfuss Gerd
Publication year - 2008
Publication title -
european journal of heart failure
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.149
H-Index - 133
eISSN - 1879-0844
pISSN - 1388-9842
DOI - 10.1016/j.ejheart.2008.02.013
Subject(s) - celecoxib , protein kinase b , medicine , muscle hypertrophy , heart failure , pressure overload , phosphorylation , endocrinology , biology , cardiac hypertrophy , microbiology and biotechnology
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.