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          Institute: MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut)     Collection: Publikationen des W. G. Kerckhoff-Instituts     Display Documents



ID: 428397.0, MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut) / Publikationen des W. G. Kerckhoff-Instituts
Combined tyrosine and serine/threonine kinase inhibition by sorafenib prevents progression of experimental pulmonary hypertension and myocardial remodeling
Authors:Klein, M.; Schermuly, R. T.; Ellinghaus, P.; Milting, H.; Riedl, B.; Nikolova, S.; Pullamsetti, S. S.; Weissmann, N.; Dony, E.; Savai, R.; Ghofrani, H. A.; Grimminger, F.; Busch, A. E.; Schafer, S.
Date of Publication (YYYY-MM-DD):2008
Title of Journal:Circulation
Volume:118
Issue / Number:20
Start Page:2081
End Page:2090
Audience:Not Specified
Abstract / Description:BACKGROUND: Inhibition of tyrosine kinases, including platelet-derived growth factor receptor, can reduce pulmonary arterial pressure in experimental and clinical pulmonary hypertension. We hypothesized that inhibition of the serine/threonine kinases Raf-1 (also termed c-Raf) and b-Raf in addition to inhibition of tyrosine kinases effectively controls pulmonary vascular and right heart remodeling in pulmonary hypertension. METHODS AND RESULTS: We investigated the effects of the novel multikinase inhibitor sorafenib, which inhibits tyrosine kinases as well as serine/threonine kinases, in comparison to imatinib, a tyrosine kinase inhibitor, on hemodynamics, pulmonary and right ventricular (RV) remodeling, and downstream signaling in experimental pulmonary hypertension. Fourteen days after monocrotaline injection, male rats were treated orally for another 14 days with sorafenib (10 mg/kg per day), imatinib (50 mg/kg per day), or vehicle (n=12 to 16 per group). RV systolic pressure was decreased to 35.0+/-1.5 mm Hg by sorafenib and to 54.0+/-4.4 mm Hg by imatinib compared with placebo (82.9+/-6.0 mm Hg). In parallel, both sorafenib and imatinib reduced RV hypertrophy and pulmonary arterial muscularization. The effects of sorafenib on RV systolic pressure and RV mass were significantly greater than those of imatinib. Sorafenib prevented phosphorylation of Raf-1 and suppressed activation of the downstream ERK1/2 signaling pathway in RV myocardium and the lungs. In addition, sorafenib but not imatinib antagonized vasopressin-induced hypertrophy of the cardiomyoblast cell line H9c2. CONCLUSIONS: The multikinase inhibitor sorafenib prevents pulmonary remodeling and improves cardiac and pulmonary function in experimental pulmonary hypertension. Sorafenib exerts direct myocardial antihypertrophic effects, which appear to be mediated via inhibition of the Raf kinase pathway. The combined inhibition of tyrosine and serine/threonine kinases may provide an option to treat pulmonary arterial hypertension and associated right heart remodeling.
Free Keywords:Animals Benzenesulfonates/*pharmacology Blood Pressure/drug effects Disease Progression Extracellular Signal-Regulated MAP Kinases/metabolism Heart/drug effects/physiopathology Heart Ventricles Hypertension, Pulmonary/*physiopathology Lung/drug effects/physiopathology Male Phosphorylation/drug effects Piperazines/pharmacology Protein Kinase Inhibitors/*pharmacology Protein-Tyrosine Kinases/*antagonists & inhibitors Proto-Oncogene Proteins c-raf/antagonists & inhibitors Pulmonary Artery/drug effects/physiopathology Pyridines/*pharmacology Pyrimidines/pharmacology Rats Rats, Sprague-Dawley Signal Transduction/drug effects Ventricular Remodeling/*drug effects raf Kinases/*antagonists & inhibitors
External Publication Status:published
Document Type:Article
Communicated by:N. N.
Affiliations:MPI für physiologische und klinische Forschung
Identifiers:URL:http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=...
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