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

Thomas Bertero


Yu Lu

Sofia Annis


Andrew Hale

Balkrishen Bhat


Rajan Saggar


Rajeev Saggar


Dean Wallace


David Ross


Sarah Vargas


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Conference: 2014 International PHA Conference and Scientific Sessions

Release Date: 06.22.2014

Presentation Type: Abstracts

File Download: 2014 Conference Abstract - Stephen Chan

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Pulmonary hypertension (PH) is a complex vascular disease involving disparate molecular pathways spanning multiple cell types. MicroRNAs (miRNAs) are small non-coding RNAs that may coordinately regulate these processes, but their integrative functions have been challenging to define with conventional approaches.

Background: Pulmonary hypertension (PH) is a complex vascular disease involving disparate molecular pathways spanning multiple cell types. MicroRNAs (miRNAs) are small non-coding RNAs that may coordinately regulate these processes, but their integrative functions have been challenging to define with conventional approaches. We have hypothesized that a few unique microRNAs (miRNAs) may act as master “lynchpins” of PH, regulating many targets and even subordinate miRNAs to control downstream pathophenotypes more robustly. 

Methods and Results: We designed a novel network-based bioinformatics approach to rank miRNAs that robustly control PH by their predicted recognition of multiple targets in the same functional network of downstream PH-relevant effector genes, as derived by literature curation and mapped using consolidated databases of molecular interactions. Guided by analysis of the molecular network architecture specific to PH, the four miR-130/301 family members were predicted as master regulators of cellular proliferation and vasomotor tone in PH via control of subordinate miRNA pathways with previously unidentified connections to one another. In validation of this model, in primary cultured human pulmonary vascular cells (endothelial, smooth muscle, and fibroblasts), hypoxia or inflammatory cytokines induced a coordinated increase of these miRNAs, as measured by RT-PCR. Correspondingly, in diseased pulmonary vasculature and plasma from rodents and humans, these miRNAs were increased, as reflected by quantitative in situ stain. These miRNAs directly targeted PPARγ but with distinct cell-type-specific molecular consequences. In pulmonary arterial endothelial cells, these microRNAs induced the apelin-miR-424/503-FGF2 signaling pathway, leading to proliferation and vasoconstriction via endothelin-1 release. Separately, in pulmonary arterial smooth muscle cells, these miRNAs increased proliferation by activating a STAT3-miR-204 regulatory axis. In vivo, intratracheal delivery of miR-130a oligonucleotide mimics in the pulmonary vessels of mice repressed PPARγ and promoted PH, as reflected by increased right ventricular systolic pressure (RVSP 27.0 mmHg + 3.6 SD for miR-130 mimic [N=13 mice] versus 20.3 mmHg + 1.7 SD for control miRNA mimic [N=11 mice]) and vascular remodeling. Activation of PPAγ via rosiglitazone reversed these pathophenotypes, thus demonstrating the critical importance of PPARγ to the actions of this miRNA family. Finally, after PH initiation in mice (hypoxia + SU5416), coordinated pharmacologic inhibition of these miRNAs via antisense oligonucleotides increased PPARγ and protected against PH (RVSP 29.7 mmHg + 1.6 for anti-130 oligonucleotide [N=7 mice] versus 38.6 mmHg + 3.6 for control [N=7 mice]).

Conclusions: Such results clarify our deficient understanding of the systems-level regulation of miRNA-disease gene networks in PH with broad implications on miRNA-based therapeutics in this disease. Furthermore, these findings provide critical validation for the evolving application of network theory to the discovery of the miRNA-based origins of PH and other diseases.