Prevention of pulmonary vascular and myocardial remodeling by the combined tyrosine and serine-/threonine kinase inhibitor, sorafenib, in pulmonary hypertension and right heart failure
| Autor: | M. Klein, R. T. Schermuly, P. Ellinghaus, H. Milting, B. Riedl, H. A. Ghofrani, F. Grimminger, S. Schäfer |
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| Jazyk: | angličtina |
| Rok vydání: | 2008 |
| Předmět: | |
| Zdroj: | European Respiratory Review, Vol 17, Iss 108, Pp 72-73 (2008) |
| Druh dokumentu: | article |
| ISSN: | 0905-9180 1600-0617 |
| Popis: | Inhibition of tyrosine kinases can reverse pulmonary hypertension but little is known about the role of serine-/threonine kinases in vascular and myocardial remodeling. We investigated the effects of sorafenib, an inhibitor of the tyrosine kinases VEGFR, PDGFR and c-kit as well as the serine-/threonine kinase Raf-1, in pulmonary hypertension and right ventricular (RV) pressure overload. In monocrotaline treated rats, sorafenib (10 mg·kg–1·d–1 p.o.) reduced pulmonary arterial pressure, pulmonary artery muscularization and RV hypertrophy, and improved systemic hemodynamics (table 1). Sorafenib prevented phosphorylation of Raf-1 and suppressed activation of downstream signaling pathways (Erk 1/2). After pulmonary banding, sorafenib, but not the PDGFR/c-KIT/ABL-inhibitor imatinib reduced RV mass and RV filling pressure significantly. Congruent with these results, sorafenib only prevented ERK phosphorylation and vasopressin induced hypertrophy of the cardiomyocyte cell line H9c2 dose dependently (IC50 = 300 nM). Combined inhibition of tyrosine and serine-/threonine kinases by sorafenib prevents vascular and cardiac remodeling in pulmonary hypertension, which is partly mediated via inhibition of the Raf kinase pathway. |
| Databáze: | Directory of Open Access Journals |
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