Conference: 2012 International PHA Conference and Scientific Sessions
Release Date: 06.22.2012
Presentation Type: Abstracts
BACKGROUND: PAH is a life-threatening condition characterized by pulmonary arteriolar remodeling, progressive elevation of pulmonary artery pressure, and right heart failure. The genomic mechanisms of PAH remain ill defined. We have recently reported genome-wide lung tissue mRNA expression changes associated with PAH and pulmonary hypertension (PH) associated with idiopathic pulmonary fibrosis (IPF). We hypothesize that microRNAs regulate many of these mRNA expression changes. We therefore determined genome-wide microRNA expression changes.
METHODS AND RESULTS: Using microarrays, we generated microRNA expression profiles in lung tissue from subjects with PAH (n = 18), PH associated with IPF (n = 5), and normal controls (n = 10). Expression of 23 microRNAs was significantly increased in PAH relative to normal controls, with miR-101*, miR-33a and miR-144 and miR-410 appearing to be key players in the pathogenesis of PAH. mRNA targets were predicted for 21 of these 23 microRNAs using two independent computational models and Ingenuity Pathway Analysis and these data were integrated with our previously published mRNA expression data from the same subjects. Our analysis suggested that microRNAs were involved in the pathogenesis of PAH by altering cellular growth and proliferation, protein ubiquitination, and TGF-β (BMPR2, BMPR1A, ACVR1, SMAD2/4), ERK/MAPK, β-adrenergic, and PDGF signaling.
CONCLUSIONS: This is the first study to integrate genome-wide mRNA and microRNA expression data in PAH. The present study identifies a set of microRNAs that appear to regulate many of the changes in mRNA expression and perturbation of biological pathways that we previously observed in PAH. We also successfully validated the application of a novel computational model for mRNA target prediction on clinically acquired mRNA and microRNA expression data.