Abstract
Background: We previously described that PECAM+ circulating endothelial microparticles (EMPs) are elevated in bicuspid aortic valve (BAV) disease as a manifestation of endothelial damage. In this study, we hypothesized that this endothelial damage, is functionally related to the secretion of a specific pattern of EMP-associated miRNAs.Methods: We used a bioinformatics approach to correlate the PECAM+ EMP levels with the miRNA expression profile in plasma in healthy individuals and BAV patients (n = 36). In addition, using the miRNAs that were significantly associated with PECAM+ EMP levels, we inferred a miRNA co-expression network using a Gaussian graphical modeling approach to identify highly co-expressed miRNAs or miRNA clusters whose expression could functionally regulate endothelial damage.Results: We identified a co-expression network composed of 131 miRNAs whose circulating expression was significantly associated with PECAM+ EMP levels. Using a topological analysis, we found that miR-494 was the most important hub within the co-expression network. Furthermore, through positional gene enrichment analysis, we identified a cluster of 19 highly co-expressed miRNAs, including miR-494, that was located in the 14q32 locus on chromosome 14 (p = 1.9 × 10−7). We evaluated the putative biological role of this miRNA cluster by determining the biological significance of the genes targeted by the cluster using functional enrichment analysis. We found that this cluster was involved in the regulation of genes with various functions, specifically the “cellular nitrogen compound metabolic process” (p = 2.34 × 10−145), “immune system process” (p = 2.57 × 10−6), and “extracellular matrix organization” (p = 8.14 × 10−5) gene ontology terms and the “TGF-β signaling pathway” KEGG term (p = 2.59 × 10−8).Conclusions: Using an integrative bioinformatics approach, we identified the circulating miRNA expression profile associated with secreted PECAM+ EMPs in BAV disease. Additionally, we identified a highly co-expressed miRNA cluster that could mediate crucial biological processes in BAV disease, including the nitrogen signaling pathway, cellular activation, and the transforming growth factor beta signaling pathway. In conclusion, EMP-associated and co-expressed miRNAs could act as molecular effectors of the intercellular communication carried out by EMPs in response to endothelial damage.
Highlights
Bicuspid aortic valve (BAV), the most common cardiac congenital malformation, is associated with valve dysfunction and is a risk factor for aortopathy (Tzemos et al, 2008; Alegret et al, 2013)
To explore the circulating PECAM+ endothelial microparticles (EMPs)-associated Micro-ribonucleic acids (miRNAs), we first corroborated our previously reported finding that BAV patients have increased levels of PECAM+ EMPs in plasma compared with tricuspid aortic valve (TAV) healthy controls (Supplementary Figure 1A)
The results of this analysis supported the role of PECAM+ EMP circulating levels as a biomarker of aortic dilation in BAV disease, as an increased diameter of the aortic root or ascending aorta was associated with higher levels of PECAM+ EMPs (Supplementary Figure 1B)
Summary
Bicuspid aortic valve (BAV), the most common cardiac congenital malformation (occurs in 1–2% of the population), is associated with valve dysfunction and is a risk factor for aortopathy (Tzemos et al, 2008; Alegret et al, 2013). We reported that circulating endothelial microparticles (EMPs) are elevated in BAV patients and related to aortic dilation (Alegret et al, 2016). We identified PECAM+ EMPs, which are a kind of EMP that express CD31 and are released in endothelial damage, as those related to BAV disease. We previously described that PECAM+ circulating endothelial microparticles (EMPs) are elevated in bicuspid aortic valve (BAV) disease as a manifestation of endothelial damage. We hypothesized that this endothelial damage, is functionally related to the secretion of a specific pattern of EMP-associated miRNAs
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