MicroRNA-223 regulates Glut4 expression and cardiomyocyte glucose metabolism.
Cardiovasc Res
; 86(3): 410-20, 2010 Jun 01.
Article
em En
| MEDLINE
| ID: mdl-20080987
ABSTRACT
AIMS:
MicroRNAs (miRNAs) are important for cardiac function and tissue metabolism. The aim of the present study is to investigate the role(s) of miRNAs in the insulin-resistant heart. METHODS ANDRESULTS:
Left ventricular biopsies were collected from patients with or without type 2 diabetes and from patients with left ventricular dysfunction. Quantitative miRNA expression analyses of 155 miRNAs revealed that miR-223 was consistently upregulated in the insulin-resistant heart. We assessed the effects of miR-223 on glucose metabolism in neonatal rat cardiomyocytes where adenoviral-mediated overexpression of miR-223 increased glucose uptake. Using in silico miRNA target prediction programs, we prioritized candidate miR-223 target genes, but observed no effect of miR-223 on myocyte enhancer factor 2c or insulin-like growth factor 1 receptor, and an unexpected miR-223-induced increase in nuclear factor IA. We next examined the effects of miR-223 on insulin signalling and glucose transport proteins. Neither phosphoinositide 3-kinase (PI3K) signalling nor AMP kinase activity was affected by miR-223 overexpression, whereas glucose transporter 4 (Glut4) protein expression was increased. miR-223 overexpression-induced Glut4 protein expression in cardiomyocytes was necessary and sufficient for increased glucose uptake as demonstrated by siRNA knockdown of Glut4. Loss-of-function studies in vivo, using a synthetic miR-223 inhibitor, confirmed the effect of miR-223 on Glut4.CONCLUSION:
These data demonstrate a role for miR-223 in Glut4 regulation and glucose metabolism in the heart, reveal the pleiotropic effects of miRNAs across tissues, and show that miRNAs can upregulate target genes in terminally differentiated cardiomyocytes.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Resistência à Insulina
/
Disfunção Ventricular Esquerda
/
Miócitos Cardíacos
/
MicroRNAs
/
Diabetes Mellitus Tipo 2
/
Transportador de Glucose Tipo 4
/
Glucose
Tipo de estudo:
Observational_studies
/
Prognostic_studies
/
Risk_factors_studies
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2010
Tipo de documento:
Article