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 AND RESULTS: 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.
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