Fibroblast growth factor 21 protects the heart from angiotensin II-induced cardiac hypertrophy and dysfunction via SIRT1.
Biochim Biophys Acta Mol Basis Dis
; 1865(6): 1241-1252, 2019 06 01.
Article
em En
| MEDLINE
| ID: mdl-30677512
ABSTRACT
AIMS:
This study investigated the mechanism through which fibroblast growth factor 21 (FGF21) protects against angiotensin II (Ang II)-induced cardiac hypertrophy and dysfunction.METHODS:
Male silent information regulator 1 (SIRT1) flox/flox and cardiomyocyte-specific inducible SIRT1 knockout mice (SIRT1-iKO) were generated and treated with Ang II (1.1â¯mg/kg/day for 4â¯weeks) at the age of 8-12-week-old. FGF21 treatment [2.5â¯mg/kg/day for 4â¯weeks by intraperitoneal (i.p.) injection] was initiated at the same time as the Ang II infusion. For in vitro studies, neonatal rat cardiomyocytes (NRCMs), H9c2 rat cardiomyocytes and isolated adult mouse cardiomyocytes were treated with Ang II (1⯵M) and FGF21 (20â¯nM) for 24â¯h with or without SIRT1 silencing.RESULTS:
FGF21 treatment significantly attenuated Ang II-induced cardiac hypertrophy and dysfunction. SIRT1 knockout abolished the ability of FGF21 to prevent Ang II-induced cardiac hypertrophy, fibrosis, and apoptosis, without affecting the beneficial effects of FGF21 in Ang II-induced hypertension, and did not influence the hypertension itself. FGF21 markedly increased the deacetylase activity of SIRT1 and promoted the interaction of SIRT1 with liver kinase B1 (LKB1) and forkhead box protein O1 (FoxO1), resulting in decreased acetylation of these SIRT1 target proteins. Consequently, FGF21 promoted the activation of the LKB1 target adenosine monophosphate-activated protein kinase (AMPK) and altered the transcriptional activity of FoxO1 on its downstream target genes catalase (Cat), MnSOD (Sod2), and Bim, resulting in reduced reactive oxygen species (ROS) accumulation and cardiomyocyte apoptosis.CONCLUSIONS:
FGF21 improves cardiac function and alleviates Ang II-induced cardiac hypertrophy in a SIRT1-dependent manner.Palavras-chave
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Base de dados:
MEDLINE
Assunto principal:
Cardiomegalia
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Miócitos Cardíacos
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Sirtuína 1
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Fatores de Crescimento de Fibroblastos
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article