MicroRNAs (miRNAs) are endogenous, non-coding RNA species that regulate gene
expression at the post-transcriptional level. Recent studies have shown that miRNAs are
important for cardiac hypertrophy and heart failure, and are critical determinants of
tissue metabolism.
To investigate the role(s) of miRNAs in the insulin resistant heart, left ventricular
biopsies were collected from patients with normal ventricular function with or without
type 2 diabetes, and patients with left ventricular dysfunction (LVD). Using TaqMan
based reverse transcriptase PCR, quantitative expression levels of 155 mature miRNAs
in normal and diabetic hearts were determined. Five miRNAs were significantly
upregulated in the diabetic human heart. Among these, miR-223 was upregulated in
both diabetic heart and patients with LVD. Adenoviral-mediated overexpression of
miR-223 increased baseline glucose uptake in cardiac myocytes in vitro with an effect
size similar to that observed for insulin stimulation. This increase was associated with
increase in Glut4 protein expression but independent of PI3K/Akt signalling and AMPK
activity. In contrast to findings in other cells, in cardiac myocytes miR-223 did not
downregulate protein levels of Mef2c or Igf1r, and an unexpected increase in NfIa
protein was observed, where all three genes are miR-223 targets in immune cells.
Systemic inhibition of miR-223 in vivo decreased blood glucose level 48 hours after
administration and increased Glut4 protein level in the skeletal muscle, however Glut4
levels were decreased in the heart. Cardiac-specific transgenic mice overexpressing
miR-223 showed no detectable changes in Glut4 protein level and cardiac insulin
signalling at baseline.
Collectively, these data characterise the expression of miRNAs in the human heart,demonstrate that miRNAs regulate gene targets in a cell/tissue type specific manner,
they can unexpectedly increase protein expression in cardiac myocytes, and miR-223
regulates cardiac glucose metabolism through a non-canonical pathway, which may
have implications for future investigations and treatment of insulin resistance.