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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

Heatmap of differentially expressed miRNAs in aortic stenosis (adjusted p-value <0.05).Hierarchical clustering shows clear grouping according to presence or absence of aortic stenosis. The aortic stenosis samples to the right of the figure are outliers on the principal components analysis plot (Supplementary Figure 1 and Supplemental movie), but still cluster with other aortic stenosis samples on the first principal component. The miRNAs are listed in Supplementary Table 1.
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f1: Heatmap of differentially expressed miRNAs in aortic stenosis (adjusted p-value <0.05).Hierarchical clustering shows clear grouping according to presence or absence of aortic stenosis. The aortic stenosis samples to the right of the figure are outliers on the principal components analysis plot (Supplementary Figure 1 and Supplemental movie), but still cluster with other aortic stenosis samples on the first principal component. The miRNAs are listed in Supplementary Table 1.

Mentions: Whole miRNome profiles of 15 severely diseased aortic valve leaflets were compared to 16 control valves. After quality filtering and normalization using robust multi-array averaging, 106 miRNAs were differentially expressed between the AS and control groups at a multiple testing adjusted p-value <0.05 (Supplementary Table S1). The majority (80/106) of miRNAs were down-regulated in stenotic aortic valve tissue. Using these differentially expressed miRNAs, the miRNA profile clearly distinguished those with and without AS using hierarchical clustering (Fig. 1) and principal components analysis (Supplementary Fig. S1).


Integrated microRNA and messenger RNA analysis in aortic stenosis
Heatmap of differentially expressed miRNAs in aortic stenosis (adjusted p-value <0.05).Hierarchical clustering shows clear grouping according to presence or absence of aortic stenosis. The aortic stenosis samples to the right of the figure are outliers on the principal components analysis plot (Supplementary Figure 1 and Supplemental movie), but still cluster with other aortic stenosis samples on the first principal component. The miRNAs are listed in Supplementary Table 1.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f1: Heatmap of differentially expressed miRNAs in aortic stenosis (adjusted p-value <0.05).Hierarchical clustering shows clear grouping according to presence or absence of aortic stenosis. The aortic stenosis samples to the right of the figure are outliers on the principal components analysis plot (Supplementary Figure 1 and Supplemental movie), but still cluster with other aortic stenosis samples on the first principal component. The miRNAs are listed in Supplementary Table 1.
Mentions: Whole miRNome profiles of 15 severely diseased aortic valve leaflets were compared to 16 control valves. After quality filtering and normalization using robust multi-array averaging, 106 miRNAs were differentially expressed between the AS and control groups at a multiple testing adjusted p-value <0.05 (Supplementary Table S1). The majority (80/106) of miRNAs were down-regulated in stenotic aortic valve tissue. Using these differentially expressed miRNAs, the miRNA profile clearly distinguished those with and without AS using hierarchical clustering (Fig. 1) and principal components analysis (Supplementary Fig. S1).

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