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(Circulation. 2008;118:2081-2090.)
© 2008 American Heart Association, Inc.

Vascular Medicine

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; 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.

Correspondence to Stefan Schäfer, MD, Cardiology Research, Bayer Schering Pharma, Aprather Weg 18a, 42096 Wuppertal, Germany. E-mail Stefan.schaefer{at}bayerhealthcare.com

Received November 8, 2007; accepted September 11, 2008.

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.

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CLINICAL PERSPECTIVE

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Clinical Summaries
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