Crosstalk between AMPK activation and angiotensin II-induced hypertrophy in cardiomyocytes: the role of mitochondria.
J Cell Mol Med
; 18(4): 709-20, 2014 Apr.
Article
en En
| MEDLINE
| ID: mdl-24444314
ABSTRACT
AMP-kinase (AMPK) activation reduces cardiac hypertrophy, although underlying molecular mechanisms remain unclear. In this study, we elucidated the anti-hypertrophic action of metformin, specifically, the role of the AMPK/eNOS/p53 pathway. H9c2 rat cardiomyocytes were treated with angiotensin II (AngII) for 24 hrs in the presence or absence of metformin (AMPK agonist), losartan [AngII type 1 receptor (AT1R) blocker], Nω-nitro-L-arginine methyl ester (L-NAME, pan-NOS inhibitor), splitomicin (SIRT1 inhibitor) or pifithrin-α (p53 inhibitor). Results showed that treatment with metformin significantly attenuated AngII-induced cell hypertrophy and death. Metformin attenuated AngII-induced activation (cleavage) of caspase 3, Bcl-2 down-regulation and p53 up-regulation. It also reduced AngII-induced AT1R up-regulation by 30% (P < 0.05) and enhanced AMPK phosphorylation by 99% (P < 0.01) and P-eNOS levels by 3.3-fold (P < 0.01). Likewise, losartan reduced AT1R up-regulation and enhanced AMPK phosphorylation by 54% (P < 0.05). The AMPK inhibitor, compound C, prevented AT1R down-regulation, indicating that metformin mediated its effects via AMPK activation. Beneficial effects of metformin and losartan converged on mitochondria that demonstrated high membrane potential (Δψm ) and low permeability transition pore opening. Thus, this study demonstrates that the anti-hypertrophic effects of metformin are associated with AMPK-induced AT1R down-regulation and prevention of mitochondrial dysfunction through the SIRT1/eNOS/p53 pathway.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Angiotensina II
/
Cardiomegalia
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Miocitos Cardíacos
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Proteínas Quinasas Activadas por AMP
/
Mitocondrias
Límite:
Animals
Idioma:
En
Revista:
J Cell Mol Med
Asunto de la revista:
BIOLOGIA MOLECULAR
Año:
2014
Tipo del documento:
Article
País de afiliación:
Estados Unidos