Published Online
on October 27, 2008

A more recent version of this article appeared on November 11, 2008

This Article Full Text (PDF) All Versions of this Article: 118/20/2081    most recent CIRCULATIONAHA.108.779751v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Klein, M. Articles by Schäfer, S. Search for Related Content PubMed PubMed Citation Articles by Klein, M. Articles by Schäfer, S. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB IMATINIB MESYLATE Medline Plus Health Information Pulmonary Hypertension Related Collections Other heart failure Remodeling Animal models of human disease Pulmonary circulation and disease Related Article

Submitted on November 8, 2007
Accepted on September 11, 2008

Combined Tyrosine and Serine/Threonine Kinase Inhibition by Sorafenib Prevents Progression of Experimental Pulmonary Hypertension and Myocardial Remodeling

Martina Klein DVM, Ralph T. Schermuly PhD, Peter Ellinghaus PhD, Hendrik Milting PhD, Bernd Riedl PhD, Sevdalina Nikolova MSc, Soni S. Pullamsetti PhD, Norbert Weissmann PhD, Eva Dony DVM, Rajkumar Savai PhD, Hossein A. Ghofrani MD, Friedrich Grimminger PhD, MD, Andreas E. Busch PhD, and Stefan Schäfer MD^*

From Cardiology Research, Bayer Schering Pharma, Wuppertal (M.K., B.R., A.E.B., S.S.); Max-Planck Institute for Heart and Lung Research, Bad Nauheim (R.T.S.); University of Giessen Lung Center, Giessen (R.T.S., S.N., S.S.P., N.W., E.D., R.S., H.A.G., F.G.); Target Discovery, Bayer Schering Pharma, Wuppertal (P.E.); and Heart and Diabetes Center NRW, Bad Oeynhausen (H.M.), Germany.

^* To whom correspondence should be addressed. E-mail: Stefan.schaefer{at}bayerhealthcare.com.

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.

Key words: hypertension, pulmonary • monocrotaline • pulmonary heart disease • remodeling • sorafenib

Related Article:

Clinical Summaries
Circulation 2008 118: 2013-2014. [Extract] [Full Text]

This article has been cited by other articles:

				K. R. Stenmark, B. Meyrick, N. Galie, W. J. Mooi, and I. F. McMurtry Animal models of pulmonary arterial hypertension: the hope for etiological discovery and pharmacological cure Am J Physiol Lung Cell Mol Physiol, December 1, 2009; 297(6): L1013 - L1032. [Abstract] [Full Text] [PDF]

				H. Yoshida, T. Kitaichi, M. Urata, H. Kurobe, T. Kanbara, T. Motoki, and T. Kitagawa Syngeneic bone marrow mononuclear cells improve pulmonary arterial hypertension through vascular endothelial growth factor upregulation. Ann. Thorac. Surg., August 1, 2009; 88(2): 418 - 424. [Abstract] [Full Text] [PDF]

				S. Schafer, P. Ellinghaus, W. Janssen, F. Kramer, K. Lustig, H. Milting, R. Kast, and M. Klein Chronic inhibition of phosphodiesterase 5 does not prevent pressure-overload-induced right-ventricular remodelling Cardiovasc Res, April 1, 2009; 82(1): 30 - 39. [Abstract] [Full Text] [PDF]