Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Jacobshagen, C; Grüber, M; Teucher, N; Schmidt, AG; Unsöld, BW; Toischer, K; Nguyen, VP; Maier, LS; Kögler, H; Hasenfuss, G.
Celecoxib modulates hypertrophic signalling and prevents load-induced cardiac dysfunction.
Eur J Heart Fail. 2008; 10(4): 334-342.
Doi: 10.1016/j.ejheart.2008.02.013
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- Co-Autor*innen der Med Uni Graz
- Schmidt Albrecht
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- 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 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.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals -
- Blood Pressure - drug effects Blood Pressure - physiology
- Cardiomyopathy, Dilated - pathology Cardiomyopathy, Dilated - physiopathology
- Cardiomyopathy, Hypertrophic - pathology Cardiomyopathy, Hypertrophic - physiopathology
- Cyclooxygenase Inhibitors - pharmacology
- Dose-Response Relationship, Drug -
- Enzyme Activation - drug effects
- Female -
- Glycogen Synthase Kinase 3 - metabolism
- Heart Failure - pathology Heart Failure - physiopathology
- Insulin - pharmacology
- Mice -
- Mice, Inbred C57BL -
- Muscle Proteins - metabolism
- Myocardial Contraction - drug effects Myocardial Contraction - physiology
- Myocytes, Cardiac - drug effects Myocytes, Cardiac - physiology
- Natriuretic Peptide, Brain - metabolism
- PTEN Phosphohydrolase - metabolism
- Phenylephrine - pharmacology
- Phosphorylation -
- Proto-Oncogene Proteins c-akt - antagonists and inhibitors Proto-Oncogene Proteins c-akt - physiology
- Pyrazoles - pharmacology
- Rabbits -
- Ribosomal Protein S6 Kinases, 70-kDa - metabolism
- Signal Transduction - drug effects Signal Transduction - physiology
- Sulfonamides - pharmacology
- Ventricular Dysfunction, Left - pathology Ventricular Dysfunction, Left - physiopathology
- Find related publications in this database (Keywords)
- hypertrophy
- heart failure
- celecoxib
- Akt signalling
- aortic banding