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01.12.2014 | Research article | Ausgabe 1/2014 Open Access

Journal of Cardiothoracic Surgery 1/2014

Multikinase inhibitor sorafenib prevents pressure overload-induced left ventricular hypertrophy in rats by blocking the c-Raf/ERK1/2 signaling pathway

Zeitschrift:
Journal of Cardiothoracic Surgery > Ausgabe 1/2014
Autoren:
Arezoo Daryadel, Anna Bogdanova, Max Gassmann, Xavier Mueller, Gregor Zünd, Burkhardt Seifert, Christine Lehalle, Nelly Frossard, Reza Tavakoli
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​1749-8090-9-81) contains supplementary material, which is available to authorized users.
Nelly Frossard and Reza Tavakoli contributed equally to this work.

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

Conceived and designed the experiments: RT, AD, AB. Performed the experiments: RT, AD. Analyzed and discussed the data: RT, NF, CL, BS, MG. Contributed reagents/materials/analysis tools: GZ, XM. Wrote the paper: RT, NF. All authors read and approved the final manuscript.

Abstract

Background

Left ventricular hypertrophy (LVH) is a potent risk factor for sudden death and congestive heart failure.

Methods

We tested the effect of sorafenib, a multikinase inhibitor (10 mg/kg, given orally, starting 2 days prior to banding, till sacrifice on day 14), on the development of LVH following aortic banding in rats.

Results

The latter resulted in significant LVH caused by both an increase in cardiomyocyte volume and interstitial collagen deposition. The observed LVH was entirely blocked by sorafenib downregulating both of these components. LVH was associated with PDGF-BB and TGFβ1 overexpression, as well as phosphorylation of c-raf and ERK1/2. Additionally, the transcription factors c-myc and c-fos leading to proliferation as well as the hypertrophy-inducing transcription factor GATA4 and its regulated gene ANP were all upregulated in response to aortic banding. All these overexpressions and upregulations were inhibited upon sorafenib treatment.

Conclusion

We show that sorafenib exhibits a regulatory role on the occurrence of LVH following AB in rats by blocking the rise in growth factors PDGF-BB and TGFβ1, activation of the corresponding c-Raf-ERK1/2 signaling pathway and effector mechanisms, including GATA4 and ANP. This effect of sorafenib may be of clinical importance in modulating the maladaptive hypertrophic response to pressure overload.
Zusatzmaterial
Authors’ original file for figure 1
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Authors’ original file for figure 2
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Authors’ original file for figure 3
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Authors’ original file for figure 4
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Authors’ original file for figure 5
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Authors’ original file for figure 6
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Authors’ original file for figure 7
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Literatur
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