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Cardiomyocyte BRAF and type 1 RAF inhibitors promote cardiomyocyte and cardiac hypertrophy in mice in vivo

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Title: Cardiomyocyte BRAF and type 1 RAF inhibitors promote cardiomyocyte and cardiac hypertrophy in mice in vivo
Authors: Clerk, A
Meijles, DN
Hardyman, MA
Fuller, SJ
Chothani, SP
Cull, JJ
Cooper, STE
Alharbi, HO
Vanezis, K
Felkin, LE
Markou, T
Leonard, SJ
Shaw, SW
Rackham, OJL
Cook, SA
Glennon, PE
Sheppard, MN
Sembrat, JC
Rojas, M
McTiernan, CF
Barton, PJ
Sugden, PH
Item Type: Journal Article
Abstract: The extracellular signal-regulated kinase 1/2 (ERK1/2) cascade promotes cardiomyocyte hypertrophy and is cardioprotective, with the three RAF kinases forming a node for signal integration. Our aims were to determine if BRAF is relevant for human heart failure, whether BRAF promotes cardiomyocyte hypertrophy, and if Type 1 RAF inhibitors developed for cancer (that paradoxically activate ERK1/2 at low concentrations: the 'RAF paradox') may have the same effect. BRAF was up-regulated in heart samples from patients with heart failure compared with normal controls. We assessed the effects of activated BRAF in the heart using mice with tamoxifen-activated Cre for cardiomyocyte-specific knock-in of the activating V600E mutation into the endogenous gene. We used echocardiography to measure cardiac dimensions/function. Cardiomyocyte BRAFV600E induced cardiac hypertrophy within 10 d, resulting in increased ejection fraction and fractional shortening over 6 weeks. This was associated with increased cardiomyocyte size without significant fibrosis, consistent with compensated hypertrophy. The experimental Type 1 RAF inhibitor, SB590885, and/or encorafenib (a RAF inhibitor used clinically) increased ERK1/2 phosphorylation in cardiomyocytes, and promoted hypertrophy, consistent with a 'RAF paradox' effect. Both promoted cardiac hypertrophy in mouse hearts in vivo, with increased cardiomyocyte size and no overt fibrosis. In conclusion, BRAF potentially plays an important role in human failing hearts, activation of BRAF is sufficient to induce hypertrophy, and Type 1 RAF inhibitors promote hypertrophy via the 'RAF paradox'. Cardiac hypertrophy resulting from these interventions was not associated with pathological features, suggesting that Type 1 RAF inhibitors may be useful to boost cardiomyocyte function.
Issue Date: 11-Feb-2022
Date of Acceptance: 27-Jan-2022
URI: http://hdl.handle.net/10044/1/95107
DOI: 10.1042/BCJ20210615
ISSN: 0264-6021
Publisher: Portland Press
Start Page: 401
End Page: 424
Journal / Book Title: Biochemical Journal
Volume: 479
Issue: 3
Copyright Statement: © 2022 The Author(s). This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY). Open access for this article was enabled by the participation of University of Reading in an all-inclusive Read & Publish pilot with Portland Press and the Biochemical Society under a transformative agreement with JISC.
Imperial College Healthcare NHS Trust- BRC Funding
British Heart Foundation
Funder's Grant Number: 16CVD03
Keywords: BRAF
cardiac hypertrophy
protein kinases
cardiac hypertrophy
protein kinases
Biochemistry & Molecular Biology
03 Chemical Sciences
06 Biological Sciences
11 Medical and Health Sciences
Publication Status: Published
Conference Place: England
Open Access location: https://portlandpress.com/biochemj/article/479/3/401/230788/Cardiomyocyte-BRAF-and-type-1-RAF-inhibitors
Online Publication Date: 2022-01-27
Appears in Collections:National Heart and Lung Institute

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