ERR
HOME HELP FEEDBACK ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

EUROPEAN RESPIRATORY REVIEW, 2008;17: 72-73. doi:10.1183/09059180.00010805
© 2008 the European Respiratory Society
This Article
Right arrow Full Text Freely available
Right arrow Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Permissions
Right arrow Request Permissions
Services
Right arrow Similar articles in this journal
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Klein, M.
Right arrow Articles by Schäfer, S.
Right arrow Search for Related Content
PubMed
Right arrow Articles by Klein, M.
Right arrow Articles by Schäfer, S.

Prevention of pulmonary vascular and myocardial remodeling by the combined tyrosine and serine-/threonine kinase inhibitor, sorafenib, in pulmonary hypertension and right heart failure

M. Klein*, R. T. Schermuly, P. Ellinghaus#, H. Milting{dagger}, B. Riedl*, H. A. Ghofrani, F. Grimminger and S. Schäfer*

* Cardiology Research, Bayer Schering Pharma, Wuppertal, Germany, # Target discovery, Bayer Schering Pharma, Wuppertal, Germany, University of Giessen Lung Center, Giessen, Germany, {dagger} Heart- & Diabetes Center NRW, Bad Oeynhausen, Germany

CORRESPONDENCE: Martina Klein, Cardiology Research, Bayer Schering Pharma, Wuppertal, Germany

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).


View this table:
[in this window]
[in a new window]

  		Table 1— Control and monocrotaline(MCT) treated rats

 
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.






HOME HELP FEEDBACK ARCHIVE SEARCH TABLE OF CONTENTS
Copyright © 2008 by the European Respiratory Society.