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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

The aortic stenosis associated miRNA/upregulated mRNA subnetwork.Only mRNA upregulated more than two-fold and their immediate neighbours are shown. Labels indicate genes with two or more connections in the full miRNA/mRNA network (not shown), with the drugs that target them listed in Table 2. For comparison, transforming growth factor beta 1 (marked by the filled arrow), despite being 3.6 fold increased in severely diseased valves, has only one connection to other members of the full network. Abbreviations: CXCL12, stromal cell-derived factor 1; PTPN6, Tyrosine-protein phosphatase non-receptor type 6; S100A4, S100 calcium binding protein A4; SYK, spleen tyrosine kinase; TF, transcription factor.
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f4: The aortic stenosis associated miRNA/upregulated mRNA subnetwork.Only mRNA upregulated more than two-fold and their immediate neighbours are shown. Labels indicate genes with two or more connections in the full miRNA/mRNA network (not shown), with the drugs that target them listed in Table 2. For comparison, transforming growth factor beta 1 (marked by the filled arrow), despite being 3.6 fold increased in severely diseased valves, has only one connection to other members of the full network. Abbreviations: CXCL12, stromal cell-derived factor 1; PTPN6, Tyrosine-protein phosphatase non-receptor type 6; S100A4, S100 calcium binding protein A4; SYK, spleen tyrosine kinase; TF, transcription factor.

Mentions: For target discovery, we focused on upregulated genes in the integrated miRNA/mRNA network with fold change of two or greater. A total of 57 potential drug-gene interactions were identified in the DGIdb database that might reduce the levels of the corresponding gene products (Fig. 4). The majority of these genes are on the periphery of the network. There were only four targeted genes with two or more connections to other parts of the network (Table 4). Spleen tyrosine kinase (SYK) was the most connected targeted mRNA, and transforming growth factor (TGF)-β, while not being highly connected in the network, was also identified as a drug target.


Integrated microRNA and messenger RNA analysis in aortic stenosis
The aortic stenosis associated miRNA/upregulated mRNA subnetwork.Only mRNA upregulated more than two-fold and their immediate neighbours are shown. Labels indicate genes with two or more connections in the full miRNA/mRNA network (not shown), with the drugs that target them listed in Table 2. For comparison, transforming growth factor beta 1 (marked by the filled arrow), despite being 3.6 fold increased in severely diseased valves, has only one connection to other members of the full network. Abbreviations: CXCL12, stromal cell-derived factor 1; PTPN6, Tyrosine-protein phosphatase non-receptor type 6; S100A4, S100 calcium binding protein A4; SYK, spleen tyrosine kinase; TF, transcription factor.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f4: The aortic stenosis associated miRNA/upregulated mRNA subnetwork.Only mRNA upregulated more than two-fold and their immediate neighbours are shown. Labels indicate genes with two or more connections in the full miRNA/mRNA network (not shown), with the drugs that target them listed in Table 2. For comparison, transforming growth factor beta 1 (marked by the filled arrow), despite being 3.6 fold increased in severely diseased valves, has only one connection to other members of the full network. Abbreviations: CXCL12, stromal cell-derived factor 1; PTPN6, Tyrosine-protein phosphatase non-receptor type 6; S100A4, S100 calcium binding protein A4; SYK, spleen tyrosine kinase; TF, transcription factor.
Mentions: For target discovery, we focused on upregulated genes in the integrated miRNA/mRNA network with fold change of two or greater. A total of 57 potential drug-gene interactions were identified in the DGIdb database that might reduce the levels of the corresponding gene products (Fig. 4). The majority of these genes are on the periphery of the network. There were only four targeted genes with two or more connections to other parts of the network (Table 4). Spleen tyrosine kinase (SYK) was the most connected targeted mRNA, and transforming growth factor (TGF)-β, while not being highly connected in the network, was also identified as a drug target.

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