Header

UZH-Logo

Maintenance Infos

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


Daryadel, Arezoo; Bogdanova, Anna; Gassmann, Max; Mueller, Xavier; Zünd, Gregor; Seifert, Burkhardt; Lehalle, Christine; Frossard, Nelly; Tavakoli, Reza (2014). Multikinase inhibitor sorafenib prevents pressure overload-induced left ventricular hypertrophy in rats by blocking the c-Raf/ERK1/2 signaling pathway. Journal of Cardiothoracic Surgery, 9:81.

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.

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.

Statistics

Citations

3 citations in Web of Science®
3 citations in Scopus®
Google Scholar™

Altmetrics

Downloads

94 downloads since deposited on 10 Jun 2014
30 downloads since 12 months
Detailed statistics

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Cardiovascular Surgery
04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology

04 Faculty of Medicine > Epidemiology, Biostatistics and Prevention Institute (EBPI)
04 Faculty of Medicine > Center for Integrative Human Physiology
05 Vetsuisse Faculty > Institute of Veterinary Physiology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2014
Deposited On:10 Jun 2014 11:42
Last Modified:07 Aug 2017 05:16
Publisher:BioMed Central
ISSN:1749-8090
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1186/1749-8090-9-81
PubMed ID:24885948

Download

Preview Icon on Download
Preview
Content: Accepted Version
Filetype: PDF
Size: 1MB
View at publisher
Preview Icon on Download
Preview
Content: Published Version
Filetype: PDF
Size: 2MB
Licence: Creative Commons: Attribution 2.0 Generic (CC BY 2.0)