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Integrated microRNA and messenger RNA analysis in aortic stenosis

View Article: PubMed Central - PubMed

ABSTRACT

Aortic valve stenosis (AS) is a major cause of morbidity and mortality, with no effective medical therapies. Investigation into the underlying biology of AS in humans is limited by difficulties in obtaining healthy valvular tissue for use as a control group. However, micro-ribonucleic acids (miRNAs) are stable in post-mortem tissue. We compared valve specimens from patients undergoing aortic valve replacement for AS to non-diseased cadaveric valves. We found 106 differentially expressed miRNAs (p < 0.05, adjusted for multiple comparisons) on microarray analysis, with highly correlated expression among up- and down-regulated miRNAs. Integrated miRNA/gene expression analysis validated the microarray results as a whole, while quantitative polymerase chain reaction confirmed downregulation of miR-122-5p, miR-625-5p, miR-30e-5p and upregulation of miR-21-5p and miR-221-3p. Pathway analysis of the integrated miRNA/mRNA network identified pathways predominantly involved in extracellular matrix function. A number of currently available therapies target products of upregulated genes in the integrated miRNA/mRNA network, with these genes being predominantly more peripheral members of the network. The identification of a group of tissue miRNA associated with AS may contribute to the development of new therapeutic approaches to AS. This study highlights the importance of systems biology-based approaches to complex diseases.

No MeSH data available.


Related in: MedlinePlus

Co-expression network of differentially expressed miRNAs in aortic stenosis.Differentially expressed miRNAs (adjusted p < 0.05) in severely diseased aortic valve tissue with Pearson correlation coefficient more than 50%. Different colours distinguish the different groups identified by the Markov clustering algorithm. Boxes list the top three KEGG pathways associated with the miRNAs in each cluster by DIANA miRPath. The dashed separator is used to separate up- and down-regulated miRNAs, but the network was analysed as a whole. Abbreviations: KEGG, Kyoto Encyclopedia of Genes and Genomes; MAPK, mitogen-activated protein kinase; PI3K, phosphatidylinositol-4,5-bisphosphate 3-kinase; TGF, transforming growth factor.
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f2: Co-expression network of differentially expressed miRNAs in aortic stenosis.Differentially expressed miRNAs (adjusted p < 0.05) in severely diseased aortic valve tissue with Pearson correlation coefficient more than 50%. Different colours distinguish the different groups identified by the Markov clustering algorithm. Boxes list the top three KEGG pathways associated with the miRNAs in each cluster by DIANA miRPath. The dashed separator is used to separate up- and down-regulated miRNAs, but the network was analysed as a whole. Abbreviations: KEGG, Kyoto Encyclopedia of Genes and Genomes; MAPK, mitogen-activated protein kinase; PI3K, phosphatidylinositol-4,5-bisphosphate 3-kinase; TGF, transforming growth factor.

Mentions: Most miRNAs formed correlated clusters of expression (Supplementary Figure S2). The majority of down-regulated miRNAs showed highly correlated expression (Pearson correlation coefficient ≥70%), with the most suppressed, miR-122-5p, at the core of the miRNA network. Up-regulated miRNAs were correlated to a lesser degree, but the majority were still correlated at a Pearson correlation coefficient ≥50%, and had miR-21-5p at the core of the major network. Network analysis with the Markov clustering algorithm showed five separate clusters of co-expressed miRNAs as well as a cluster consisting of miR-320a, -320b, and -320c (Fig. 2). Pathway analysis of the clusters showed that although there was considerable overlap, in particular with the MAPK and Pl3K-Akt signalling pathways, the clusters had a distinct set of associated pathways (Table 2), and cluster 3, which contained miR-21-5p, miR-221-3p and miR-222-3p, was most associated with TGF-β signalling (adjusted p-value 1.2 × 10−16).


Integrated microRNA and messenger RNA analysis in aortic stenosis
Co-expression network of differentially expressed miRNAs in aortic stenosis.Differentially expressed miRNAs (adjusted p < 0.05) in severely diseased aortic valve tissue with Pearson correlation coefficient more than 50%. Different colours distinguish the different groups identified by the Markov clustering algorithm. Boxes list the top three KEGG pathways associated with the miRNAs in each cluster by DIANA miRPath. The dashed separator is used to separate up- and down-regulated miRNAs, but the network was analysed as a whole. Abbreviations: KEGG, Kyoto Encyclopedia of Genes and Genomes; MAPK, mitogen-activated protein kinase; PI3K, phosphatidylinositol-4,5-bisphosphate 3-kinase; TGF, transforming growth factor.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5120312&req=5

f2: Co-expression network of differentially expressed miRNAs in aortic stenosis.Differentially expressed miRNAs (adjusted p < 0.05) in severely diseased aortic valve tissue with Pearson correlation coefficient more than 50%. Different colours distinguish the different groups identified by the Markov clustering algorithm. Boxes list the top three KEGG pathways associated with the miRNAs in each cluster by DIANA miRPath. The dashed separator is used to separate up- and down-regulated miRNAs, but the network was analysed as a whole. Abbreviations: KEGG, Kyoto Encyclopedia of Genes and Genomes; MAPK, mitogen-activated protein kinase; PI3K, phosphatidylinositol-4,5-bisphosphate 3-kinase; TGF, transforming growth factor.
Mentions: Most miRNAs formed correlated clusters of expression (Supplementary Figure S2). The majority of down-regulated miRNAs showed highly correlated expression (Pearson correlation coefficient ≥70%), with the most suppressed, miR-122-5p, at the core of the miRNA network. Up-regulated miRNAs were correlated to a lesser degree, but the majority were still correlated at a Pearson correlation coefficient ≥50%, and had miR-21-5p at the core of the major network. Network analysis with the Markov clustering algorithm showed five separate clusters of co-expressed miRNAs as well as a cluster consisting of miR-320a, -320b, and -320c (Fig. 2). Pathway analysis of the clusters showed that although there was considerable overlap, in particular with the MAPK and Pl3K-Akt signalling pathways, the clusters had a distinct set of associated pathways (Table 2), and cluster 3, which contained miR-21-5p, miR-221-3p and miR-222-3p, was most associated with TGF-β signalling (adjusted p-value 1.2 × 10−16).

View Article: PubMed Central - PubMed

ABSTRACT

Aortic valve stenosis (AS) is a major cause of morbidity and mortality, with no effective medical therapies. Investigation into the underlying biology of AS in humans is limited by difficulties in obtaining healthy valvular tissue for use as a control group. However, micro-ribonucleic acids (miRNAs) are stable in post-mortem tissue. We compared valve specimens from patients undergoing aortic valve replacement for AS to non-diseased cadaveric valves. We found 106 differentially expressed miRNAs (p&thinsp;&lt;&thinsp;0.05, adjusted for multiple comparisons) on microarray analysis, with highly correlated expression among up- and down-regulated miRNAs. Integrated miRNA/gene expression analysis validated the microarray results as a whole, while quantitative polymerase chain reaction confirmed downregulation of miR-122-5p, miR-625-5p, miR-30e-5p and upregulation of miR-21-5p and miR-221-3p. Pathway analysis of the integrated miRNA/mRNA network identified pathways predominantly involved in extracellular matrix function. A number of currently available therapies target products of upregulated genes in the integrated miRNA/mRNA network, with these genes being predominantly more peripheral members of the network. The identification of a group of tissue miRNA associated with AS may contribute to the development of new therapeutic approaches to AS. This study highlights the importance of systems biology-based approaches to complex diseases.

No MeSH data available.


Related in: MedlinePlus