The MicroRNA-130/301 Family Controls Vasoconstriction in Pulmonary Hypertension

Abstract

Background:The microRNA-130/301 family regulates pulmonary hypertension (PH), but its breadth of activity remains undefined. Results: Predicted by network analysis, microRNA-130/301 members regulate vasoactive factors such as endothelin-1 for pulmonary vascular cross-talk. Conclusion:The microRNA-130/301 family promotes vasoconstriction in PH. Significance: This microRNA-based mechanism of vascular cross-talk is central to the systems-wide actions of microRNA-130/301 in PH.

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.…”

“…Dysregulation of entire sets of circulating miRNAs in PAH has also been described (74,76). Other miRNAs with known causative actions in PAH, such as the miR-130/301 family (20) and miR-210 (14), have been found to be elevated in the pulmonary circulation of patients with PH. Moreover, differential expression of plasma miRNAs was also reported in acute pulmonary embolism (77) and chronic thromboembolic PH (78).…”

“…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.…”

“…The miR-130/301 family has been shown to control vasoconstriction in PH by stimulating production of the vasoconstrictor endothelin-1 in PAECs (20). Other miRNAs, including miR-328 and miR-190, influence vascular tone in PH by targeting K 1 and Ca 21 channels (39, 40), both of which are critical to the physiological (hypoxic) and pathological response of pulmonary arteries (41).…”

Integration of Complex Data Sources to Provide Biologic Insight into Pulmonary Vascular Disease (2015 Grover Conference Series)

“…Separately, on the basis of the remaining PH-relevant targets, we defined a role for miR-130/301 in controlling pulmonary vasomotor tone. 23,24 Finally, on the basis of an observed overlap between a fibrosis network and the PH network, accompanied by a highly ranked miRNA spanning score in both networks, we delineated a self-sustaining feedback loop driven by a central mechanosensitive YAP/TAZ-miR-130/ 301 axis, controlling extracellular matrix remodeling and vascular stiffness in PH. 9,25 In sum, as predicted by our network-based algorithms, a model was confirmed, defining the global influence of miR-130/301 on vascular proliferation (Fig.…”