Abstract 18705: The miR-130/301 Family Exerts Systems-level Regulation of Proliferation, Vasoconstriction, and Extracellular Matrix Deposition to Control Pulmonary Hypertension
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 [103*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.
Author Disclosures: T. Bertero: None. K.A. Cottrill: None. Y. Lu: None. S. Annis: None. A. Hale: None. A. Krauszman: None. B. Bhat: None. R. Saggar: None. R. Saggar: None. W.D. Wallace: None. D.J. Ross: None. S.O. Vargas: None. B.B. Graham: None. R. Kumar: None. S.M. Black: None. S. Fratz: None. J.R. Fineman: None. J.D. West: None. K.J. Haley: None. A.B. Waxman: None. W.M. Kuebler: None. B.N. Chau: None. S.Y. Chan: None.
This research has received full or partial funding support from the American Heart Association
- © 2014 by American Heart Association, Inc.