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

Autor:	Clerk A; School of Biological Sciences, University of Reading, Reading, U.K., Meijles DN; Molecular and Clinical Sciences Institute, St. George's University of London, London, U.K., Hardyman MA; School of Biological Sciences, University of Reading, Reading, U.K., Fuller SJ; School of Biological Sciences, University of Reading, Reading, U.K., Chothani SP; Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore Medical School, Singapore City, Singapore., Cull JJ; School of Biological Sciences, University of Reading, Reading, U.K., Cooper STE; Molecular and Clinical Sciences Institute, St. George's University of London, London, U.K., Alharbi HO; School of Biological Sciences, University of Reading, Reading, U.K., Vanezis K; National Heart and Lung Institute, Imperial College London, London, U.K.; MRC London Institute of Medical Sciences, Imperial College London, London, U.K., Felkin LE; National Heart and Lung Institute, Imperial College London, London, U.K.; Cardiovascular Research Centre, Royal Brompton and Harefield Hospitals, London, U.K., Markou T; School of Biological Sciences, University of Reading, Reading, U.K., Leonard SJ; School of Biological Sciences, University of Reading, Reading, U.K., Shaw SW; School of Biological Sciences, University of Reading, Reading, U.K., Rackham OJL; Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore Medical School, Singapore City, Singapore., Cook SA; Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore Medical School, Singapore City, Singapore.; MRC London Institute of Medical Sciences, Imperial College London, London, U.K.; National Heart Centre Singapore, Singapore City, Singapore., Glennon PE; University Hospitals Coventry and Warwickshire, University Hospital Cardiology Department, Clifford Bridge Road, Coventry, U.K., Sheppard MN; CRY Cardiovascular Pathology Department, St. George's Healthcare NHS Trust, London, U.K., Sembrat JC; Division of Pulmonary, Allergy and Critical Care Medicine, and Dorothy P & Richard P Simmons Center for Interstitial Lung Disease, Department of Medicine, University of Pittsburgh, Pittsburgh, U.S.A., Rojas M; Division of Pulmonary, Allergy and Critical Care Medicine, and Dorothy P & Richard P Simmons Center for Interstitial Lung Disease, Department of Medicine, University of Pittsburgh, Pittsburgh, U.S.A., McTiernan CF; Heart, Lung, Blood Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, U.S.A., Barton PJ; National Heart and Lung Institute, Imperial College London, London, U.K.; Cardiovascular Research Centre, Royal Brompton and Harefield Hospitals, London, U.K., Sugden PH; School of Biological Sciences, University of Reading, Reading, U.K.
Jazyk:	angličtina
Zdroj:	The Biochemical journal [Biochem J] 2022 Feb 11; Vol. 479 (3), pp. 401-424.
DOI:	10.1042/BCJ20210615
Abstrakt:	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. (© 2022 The Author(s).)
Databáze:	MEDLINE
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