دورية أكاديمية
Cardiomyocyte BRAF and type 1 RAF inhibitors promote cardiomyocyte and cardiac hypertrophy in mice in vivo.
| العنوان: | Cardiomyocyte BRAF and type 1 RAF inhibitors promote cardiomyocyte and cardiac hypertrophy in mice in vivo. |
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| المؤلفون: | 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. |
| المصدر: | The Biochemical journal [Biochem J] 2022 Feb 11; Vol. 479 (3), pp. 401-424. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Published by Portland Press on behalf of the Biochemical Society Country of Publication: England NLM ID: 2984726R Publication Model: Print Cited Medium: Internet ISSN: 1470-8728 (Electronic) Linking ISSN: 02646021 NLM ISO Abbreviation: Biochem J Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: London, UK : Published by Portland Press on behalf of the Biochemical Society |
| مواضيع طبية MeSH: | Cardiomegaly/*pathology , MAP Kinase Signaling System/*physiology , Myocytes, Cardiac/*pathology , Proto-Oncogene Proteins B-raf/*physiology, Animals ; Carbamates/pharmacology ; Carbamates/toxicity ; Cardiomegaly/metabolism ; Cell Size/drug effects ; Cells, Cultured ; Dimerization ; Gene Knock-In Techniques ; Heart Failure/pathology ; Humans ; MAP Kinase Signaling System/drug effects ; Male ; Mice ; Mice, Inbred C57BL ; Mutation, Missense ; Myocytes, Cardiac/drug effects ; Myocytes, Cardiac/metabolism ; Point Mutation ; Protein Conformation/drug effects ; Protein Interaction Mapping ; Proto-Oncogene Proteins B-raf/genetics ; Proto-Oncogene Proteins c-raf/antagonists & inhibitors ; Proto-Oncogene Proteins c-raf/biosynthesis ; Rats ; Rats, Sprague-Dawley ; Sulfonamides/pharmacology ; Sulfonamides/toxicity |
| مستخلص: | 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).) |
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| معلومات مُعتمدة: | PG/15/24/31367 United Kingdom BHF_ British Heart Foundation; MC_U120085815 United Kingdom MRC_ Medical Research Council; 204809/Z/16/Z United Kingdom WT_ Wellcome Trust; PG/15/31/31393 United Kingdom BHF_ British Heart Foundation; FS/18/33/33621 United Kingdom BHF_ British Heart Foundation; FS/19/24/34262 United Kingdom BHF_ British Heart Foundation; PG/13/71/30460 United Kingdom BHF_ British Heart Foundation; PG/19/7/34167 United Kingdom BHF_ British Heart Foundation; PG/17/11/32841 United Kingdom BHF_ British Heart Foundation; PG/19/32/34383 United Kingdom BHF_ British Heart Foundation; SP/19/1/34461 United Kingdom BHF_ British Heart Foundation; FS/18/33/3362 United Kingdom BHF_ British Heart Foundation |
| فهرسة مساهمة: | Keywords: BRAF; cardiac hypertrophy; cardiomyocytes; inhibitors; protein kinases |
| المشرفين على المادة: | 0 (Carbamates) 0 (Sulfonamides) 8L7891MRB6 (encorafenib) EC 2.7.11.1 (BRAF protein, human) EC 2.7.11.1 (Braf protein, mouse) EC 2.7.11.1 (Braf protein, rat) EC 2.7.11.1 (Proto-Oncogene Proteins B-raf) EC 2.7.11.1 (Proto-Oncogene Proteins c-raf) EC 2.7.11.1 (Raf1 protein, human) EC 2.7.11.1 (Raf1 protein, mouse) |
| تواريخ الأحداث: | Date Created: 20220211 Date Completed: 20220304 Latest Revision: 20240824 |
| رمز التحديث: | 20240826 |
| مُعرف محوري في PubMed: | PMC8883496 |
| DOI: | 10.1042/BCJ20210615 |
| PMID: | 35147166 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1470-8728 |
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| DOI: | 10.1042/BCJ20210615 |