In:
Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 130, No. suppl_2 ( 2014-11-25)
Abstract:
Background: Pulmonary hypertension (PH) is a deadly vascular disease with enigmatic molecular origins. Facets of PH have been characterized in isolation, but many have yet to be unified by a common upstream regulator. Methods & Results: We constructed a network in silico of 247 genes and 2,274 functional interactions involved in PH. Using this model and advanced network analysis, we predicted the miR-130/301 family to have the most diverse pool of PH-relevant target genes among conserved microRNAs (miRNAs). Guided by these predictions, we found that this family was up-regulated by hypoxia, inflammatory cytokines, and factors genetically linked to PH. MiR-130/301 family members were also up-regulated in remodeled pulmonary vessels in 7 animal models and 3 human subtypes of PH. Via gain- and loss-of-function experiments in vitro , we found that miR-130/301 suppressed a cohort of PPARgamma-related targets to regulate two pro-proliferative pathways (the apelin-miR-424/503-FGF2 axis in PAECs and the STAT3-miR-204-SRC axis in PASMCs); vasomotor tone ( e.g. , endothelin-1 and endothelial nitric oxide synthase); and extracellular matrix remodeling ( e.g. , the collagen crosslinking enzyme LOX). In turn, delivery of miR-130a mimic oligonucleotides in pulmonary vessels of mice altered expression of the predicted cohort of PPARgamma-related factors, leading to increased vascular remodeling (19.62±1.36 percent muscularized arterioles for miR-130a vs. 6.98±0.55 percent for scrambled control, p 〈 0.05, mean±SEM), pulmonary vascular resistance (791±124.5 [10 3 *dyn*s*cm -5 ] for miR-130a vs. 462±25.4 for control, p 〈 0.05), and perivascular collagen deposition and cross-linking (9.67±1.24 percent of perivascular area positive for Picrosirius Red stain vs 1.24±0.15 percent for scrambled control, p 〈 0.05). After PH initiation in mice (chronic hypoxia+SU5416), coordinated inhibition of these miRNAs in vivo via antisense oligonucleotides mitigated these effects. Conclusions: We used network modeling to identify miR-130/301 as a master regulator of PH and a novel potential therapeutic target. These findings provide critical support for the evolving application of network modeling to discover the hidden molecular origins of PH and other human diseases.
Type of Medium:
Online Resource
ISSN:
0009-7322
,
1524-4539
DOI:
10.1161/circ.130.suppl_2.18705
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2014
detail.hit.zdb_id:
1466401-X
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