title: Multikinase inhibitor sorafenib prevents pressure overload-induced left ventricular hypertrophy in rats by blocking the c-Raf/ERK1/2 signaling pathway.
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.
  
  
  CONCLUSIONS
  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.
authors.forename: Arezoo
authors.initials: A
authors.lastname: Daryadel
authors.forename: Anna
authors.initials: A
authors.lastname: Bogdanova
authors.forename: Max
authors.initials: M
authors.lastname: Gassmann
authors.forename: Xavier
authors.initials: X
authors.lastname: Mueller
authors.forename: Gregor
authors.initials: G
authors.lastname: Zünd
authors.forename: Burkhardt
authors.initials: B
authors.lastname: Seifert
authors.forename: Christine
authors.initials: C
authors.lastname: Lehalle
authors.forename: Nelly
authors.initials: N
authors.lastname: Frossard
authors.affiliation: Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland. reza.tavakoli@luks.ch.
authors.forename: Reza
authors.initials: R
authors.lastname: Tavakoli
mesh_terms: D000818:Animals; D000077214:Becaplermin; D001794:Blood Pressure; D015153:Blotting, Western; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000187:drug effects*; D006352:Heart Ventricles / Q000378:metabolism / Q000503:physiopathology; D017379:Hypertrophy, Left Ventricular / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics* / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis / Q000096:biosynthesis / Q000235:genetics; D012313:RNA / Q000235:genetics*; D051381:Rats; D011917:Rats, Inbred Lew; D040262:Receptors, Vascular Endothelial Growth Factor; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D000077157:Sorafenib; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis / Q000235:genetics
chemical_list: D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D020574:Proto-Oncogene Proteins c-sis; D053773:Transforming Growth Factor beta1; D000077214:Becaplermin; D009536:Niacinamide; D012313:RNA; D000077157:Sorafenib; D040262:Receptors, Vascular Endothelial Growth Factor; D019908:Proto-Oncogene Proteins c-raf