Systems-level regulation of microRNA networks by miR-130/301 promotes pulmonary hypertension

Translational Advances in the Field of Pulmonary Hypertension.Translating MicroRNA Biology in Pulmonary Hypertension. It Will Take More Than “miR” Words

“…Not only was the miR-130/301 family identified as the top-ranked miRNA family, but also such network analyses outlined a model of downstream actions of these miRNAs to include two known proliferative pathways, a pathway influencing vasoconstriction, and a novel signaling mechanism controlling extracellular matrix deposition and remodeling. These findings were verified in vivo and in vitro (15,19,20,24,31), thus demonstrating the power of combining computational bioinformatics with experimental biology and affording distinct advantages as compared with traditional scientific approaches. Network gene analyses may be applied to the current challenges of understanding the collective actions of PH-specific miRNAs on overall disease manifestation rather than merely focusing on single actions of an miRNA in isolation.…”

“…Such down-regulation was accompanied by an increase in fibroblast growth factor 2 (FGF2) and fibroblast growth factor receptor 1 (FGFR1) expression and hyperproliferation of PAECs and PASMCs, indicating that PAEC-specific alterations in miRNAs compromise the PASMC phenotype through miRNA-dependent paracrine signaling. Similarly, the miR-130/301 family was found to be increased in PAH (19), thus repressing a cohort of target genes and subordinate miRNAs, thus affecting PASMC proliferation (19) and vasoconstriction (20). PAH-PASMCs and PAH models are also characterized by a down-regulation of miR-193.…”

“…Conversely, miR-140 has been implicated in the regulation of Smad ubiquitination regulatory factor 1 (SMURF1), an E3-ubiquitin protein ligase 1, that in turn modulates BMPR2 signaling and PAH in vivo (29). Numerous additional miRNAs implicated in PAH have been reported to respond to BMPR2 signaling, such as miR-130/301 (19), and to regulate BMPR2 directly, such as miR-21 (30).…”

“…Initial attempts to model computationally and interrogate miRNA regulatory networks in the pulmonary vasculature have yielded positive results. Chan and colleagues designed an in silico approach to rank miRNAs with systems-wide effects on known downstream PH-relevant genes and their first degree interactors, based on several independent gene network architectural parameters (19,30). Not only was the miR-130/301 family identified as the top-ranked miRNA family, but also such network analyses outlined a model of downstream actions of these miRNAs to include two known proliferative pathways, a pathway influencing vasoconstriction, and a novel signaling mechanism controlling extracellular matrix deposition and remodeling.…”

“…We overlaid the list of 85 genes onto an updated and extended PH network, constructed similarly to a previous description (19) and comprising 747 interconnected genes that represent known downstream PH-relevant genes and their first-degree interactors. In doing so, we created a subgraph of 190 genes including all 85 of the original target genes and several additional genes to create a single connected component ( Figure 3B).…”