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Title: Characterisation of microRNAs in the heart
Author: Lu, Han
ISNI:       0000 0004 2687 3133
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2009
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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.
Supervisor: Aitman, Tim ; Cook, Stuart Sponsor: Department of Health ; Medical Research Council ; British Heart Foundation
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral