Abstract 16817: Whole Blood Levels of Microrna-34a-5p Predict Survival and Regulate Genes Associated With Pulmonary Arterial Hypertension
Rationale: Despite advanced therapies for pulmonary arterial hypertension (PAH) the progressive hyperproliferative pulmonary vasculopathy persists, and there remains no pharmacological cure for PAH. Circulatory microRNAs (miRs) offer considerable promise as both a prognostic biomarker, and to identify molecular mechanisms in patients with PAH. Previous miRNA microarray studies from our lab on whole blood from patients with PAH identified miR-34a as down-regulated in disease.
Objectives: To validate changes in circulating miR-34a in whole blood from patients with PAH and relate them to disease severity and survival, and determine the phenotypic effect on human pulmonary artery smooth muscle cells (PASMC).
Methods and Results: RNA was isolated from 27 treatment-naive patients with PAH, and 12 age-matched healthy volunteers (HV). Circulating miR-34a-5p was measured by TaqMan PCR and found to be significantly down-regulated in PAH compared to HV (1.7-fold, p=0.0001). Receiver operating characteristic (ROC) identified miR-34a-5p levels discriminates PAH from HV (AUC = 0.86, p=0.001). Kaplan-meier survival analysis identified miR-34a-5p levels as a significant predictor of survival in patients with PAH within 5 years (p<0.05). Reduced miR-34a-5p levels were significantly lower in patients with severe PAH, as defined by a cardiac index of <2 vs >2.5 l/min/m2 (p<0.05) and N terminal pro B-type natriuretic peptide >300 vs <300 ng/l (p<0.001). miR-34a-5p as also negatively correlated with pulmonary vascular resistance (r=-0.4, p<0.05) and pulmonary arterial wedge pressure (r=-0.4, p<0.05). Transfection of PDGF-stimulated PASMC with a miR-34a-5p inhibitor in vitro significantly increased PASMC proliferation (1.9-fold, p<0.001, n=5), whereas miR-34a-5p mimic significantly suppressed (1.5-fold, p<0.05, n=5) PASMCs proliferation.
Conclusions: Circulating miR-34a-5p levels associate with disease severity and poor prognosis in PAH. Levels of miR-34a-5p regulate proliferative-phenotype in PASMC. This research identifies miR-34a-5p as a potential biomarker and subsequent network analysis may identify novel disease mechanisms. Further experiments in pre-clinical models are currently underway.
Author Disclosures: J. Lin: None. J. Iremonger: None. J.A. Pickworth: None. A.M. Rothman: None. H.L. Casbolt: None. N.D. Arnold: None. D.G. Kiely: None. A. Lawrie: None.
- © 2016 by American Heart Association, Inc.