Cardiomyocyte BRAF is a key signalling intermediate in cardiac hypertrophy in mice.
BRAF
cardiac hypertrophy
cardiomyocytes
fibrosis
hypertension
protein-serine-threonine kinases
Journal
Clinical science (London, England : 1979)
ISSN: 1470-8736
Titre abrégé: Clin Sci (Lond)
Pays: England
ID NLM: 7905731
Informations de publication
Date de publication:
30 11 2022
30 11 2022
Historique:
received:
07
09
2022
revised:
31
10
2022
accepted:
03
11
2022
pubmed:
5
11
2022
medline:
23
11
2022
entrez:
4
11
2022
Statut:
ppublish
Résumé
Cardiac hypertrophy is necessary for the heart to accommodate an increase in workload. Physiological, compensated hypertrophy (e.g. with exercise) is reversible and largely due to cardiomyocyte hypertrophy. Pathological hypertrophy (e.g. with hypertension) is associated with additional features including increased fibrosis and can lead to heart failure. RAF kinases (ARAF/BRAF/RAF1) integrate signals into the extracellular signal-regulated kinase 1/2 cascade, a pathway implicated in cardiac hypertrophy, and activation of BRAF in cardiomyocytes promotes compensated hypertrophy. Here, we used mice with tamoxifen-inducible cardiomyocyte-specific BRAF knockout (CM-BRAFKO) to assess the role of BRAF in hypertension-associated cardiac hypertrophy induced by angiotensin II (AngII; 0.8 mg/kg/d, 7 d) and physiological hypertrophy induced by phenylephrine (40 mg/kg/d, 7 d). Cardiac dimensions/functions were measured by echocardiography with histological assessment of cellular changes. AngII promoted cardiomyocyte hypertrophy and increased fibrosis within the myocardium (interstitial) and around the arterioles (perivascular) in male mice; cardiomyocyte hypertrophy and interstitial (but not perivascular) fibrosis were inhibited in mice with CM-BRAFKO. Phenylephrine had a limited effect on fibrosis but promoted cardiomyocyte hypertrophy and increased contractility in male mice; cardiomyocyte hypertrophy was unaffected in mice with CM-BRAFKO, but the increase in contractility was suppressed and fibrosis increased. Phenylephrine induced a modest hypertrophic response in female mice and, in contrast with the males, tamoxifen-induced loss of cardiomyocyte BRAF reduced cardiomyocyte size, had no effect on fibrosis and increased contractility. The data identify BRAF as a key signalling intermediate in both physiological and pathological hypertrophy in male mice, and highlight the need for independent assessment of gene function in females.
Identifiants
pubmed: 36331065
pii: 232053
doi: 10.1042/CS20220607
pmc: PMC9679367
doi:
Substances chimiques
Proto-Oncogene Proteins B-raf
EC 2.7.11.1
Phenylephrine
1WS297W6MV
Tamoxifen
094ZI81Y45
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1661-1681Subventions
Organisme : British Heart Foundation
ID : PG/13/71/30460
Pays : United Kingdom
Organisme : British Heart Foundation
ID : PG/17/11/32841
Pays : United Kingdom
Organisme : British Heart Foundation
ID : FS/18/33/33621
Pays : United Kingdom
Organisme : British Heart Foundation
ID : PG/15/24/31367
Pays : United Kingdom
Organisme : British Heart Foundation
ID : FS/19/24/34262
Pays : United Kingdom
Informations de copyright
© 2022 The Author(s).
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