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Back to 2014 Annual Meeting Abstracts


MicroRNA Profiling Of Diseased Aortic Valves
Sean Coffey1, Michael JA Williams2, Greg T. Jones2.
1John Radcliffe Hospital, Oxford, United Kingdom, 2University of Otago, Dunedin, New Zealand.

OBJECTIVE: Given an increasing number of patients requiring aortic valve replacement and the current lack of medical therapies for calcific aortic valve disease (CAVD), there is an ongoing need for investigation into the underlying pathobiology of the disease. Studies examining diseased human valves are often hampered by the lack of an appropriate control group. MicroRNAs (miRNAs) are small non-coding RNAs that reduce transcription of mRNA, and, unlike mRNA, are stable in post-mortem tissue.
METHODS: We compared 15 aortic valves removed at aortic valve replacement for severe CAVD to 16 aortic valves obtained post-mortem using microRNA microarrays (Affymetrix GeneChip miRNA 2.0). Microarray results were validated in the same samples and an additional 26 samples, using quantitative polymerase chain reaction (qPCR). Control samples were sub-classified histologically by evidence of pre-clinical disease, in the form of macroscopic thickening, microcalcification, or atherosclerotic-like plaques.
RESULTS: Microarray analysis showed that 107 miRNAs were differentially expressed between severely diseased and control specimens, with miR-122-5p being the most down-regulated (adjusted p-value 3x10-8) and miR-21-5p being the most up-regulated in diseased tissue (adjusted p-value 5x10-6). Principal components analysis showed complete segregation of the two groups based on the miRNA profile. Validation using qPCR analysis confirmed differential expression of miR-122-5p, miR-21-5p, miR-221-3p, miR-30e-5p and miR-625-5p. MiR-200c-3p was down-regulated in microarrays but was significantly up-regulated in diseased valves on qPCR analysis. None of the validated CAVD associated miRNAs showed evidence of differential expression between control valve histological sub-groups. DIANA miRPath v2.0 analysis of the miRNAs measured using qPCR showed that glycosaminoglycan biosynthesis was the KEGG pathway showing most statistical significance for upregulated miRNAs (adjusted p-value 6.7x10-14) while ubiquitin mediated proteolysis was the most statistically significant KEGG pathway affected by downregulated miRNAs (adjusted p-value 6.1x10-8).
CONCLUSIONS: A network of miRNAs are associated with the pathobiology of advanced CAVD. The finding of fibrosis-related miR-21-5p being overexpressed was expected, while the suppression of miR-122-5p is likely related to its involvement in cholesterol metabolism. MiRNA-based therapies are currently in human trials for other disease processes, and future studies are needed to investigate the therapeutic potential of manipulation of miRNA levels in CAVD.


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