Martínez-Micaelo Neus, Beltrán-Debón Raúl, Aragonés Gerard, Faiges Marta, Alegret Josep M
Grup de Recerca Cardiovascular, Institut d'Investigació Sanitària Pere Virgili, Universitat Rovira i VirgiliReus, Spain.
Servei de Cardiologia, Hospital Universitari de Sant Joan, Universitat Rovira i VirgiliReus, Spain.
Front Physiol. 2017 Sep 5;8:648. doi: 10.3389/fphys.2017.00648. eCollection 2017.
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. We used a bioinformatics approach to correlate the PECAM EMP levels with the miRNA expression profile in plasma in healthy individuals and BAV patients ( = 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. 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 ( = 1.9 × 10). 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" ( = 2.34 × 10), "immune system process" ( = 2.57 × 10), and "extracellular matrix organization" ( = 8.14 × 10) gene ontology terms and the "TGF-β signaling pathway" KEGG term ( = 2.59 × 10). 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.
我们之前描述过，血小板内皮细胞黏附分子循环内皮微粒（EMPs）在二叶式主动脉瓣（BAV）疾病中升高，这是内皮损伤的一种表现。在本研究中，我们假设这种内皮损伤在功能上与EMP相关miRNA的特定分泌模式有关。我们采用生物信息学方法，将健康个体和BAV患者（n = 36）血浆中的PECAM EMP水平与miRNA表达谱进行关联。此外，利用与PECAM EMP水平显著相关的miRNA，我们采用高斯图形建模方法推断出一个miRNA共表达网络，以识别其表达可能在功能上调节内皮损伤的高度共表达的miRNA或miRNA簇。我们确定了一个由131个miRNA组成的共表达网络，其循环表达与PECAM EMP水平显著相关。通过拓扑分析，我们发现miR - 494是共表达网络中最重要的中心节点。此外，通过位置基因富集分析，我们确定了一组19个高度共表达的miRNA，包括miR - 494，它们位于14号染色体的14q32位点（P = 1.9×10⁻⁶）。我们通过功能富集分析确定该miRNA簇靶向的基因的生物学意义，从而评估该miRNA簇的假定生物学作用。我们发现该簇参与了具有多种功能的基因的调控，特别是“细胞氮化合物代谢过程”（P = 2.34×10⁻⁵）、“免疫系统过程”（P = 2.57×10⁻⁵）和“细胞外基质组织”（P = 8.14×10⁻⁴）基因本体术语以及“TGF-β信号通路”KEGG术语（P = 2.59×10⁻⁵）。通过综合生物信息学方法，我们确定了与BAV疾病中分泌的PECAM EMPs相关的循环miRNA表达谱。此外，我们确定了一个高度共表达的miRNA簇，它可能介导BAV疾病中的关键生物学过程，包括氮信号通路、细胞激活和转化生长因子β信号通路。总之，EMP相关且共表达的miRNA可能作为EMP响应内皮损伤而进行的细胞间通讯的分子效应器。
