Abstract 14971: Role for RUNX2 in Human and Experimental Pulmonary Arterial Hypertension
Introduction: Pulmonary arterial hypertension (PAH) is a vascular remodeling disease characterized by enhanced pulmonary artery smooth muscle cells (PASMC) proliferation and suppressed apoptosis. Numerous biological pathways have been implicated in the sustainability of this phenotype, including BMPR2, HDAC, P53, the STAT3/NFAT axis along with HIF-1. Several studies have demonstrated that miR-204 is downregulated in PAH. Interestingly, miR-204 regulates the expression of the transcription factor RUNX2, which is implicated in many features characterizing PAH, including modulation of the BMP2, HIF-1, HDAC, P53 pathways. Thus we hypothesized that miR-204 downregulation in PAH triggers RUNX2 expression promoting PASMC proliferation and resistance to apoptosis.
Methods and results: Using human explanted lungs, fresh distal PAs and freshly isolated PASMC from both control and PAH patients (n=5 to 12), we demonstrated a significant (p<0.05) upregulation of RUNX2 (qRT-PCR, western blot and immunofluorescence) in PAH compared to controls. Gain and loss functions experiments in PASMC showed that downregulation of miR-204 in control PASMC increases RUNX2 expression, while increases in miR-204 in PAH-PASMC decreases it (p<0.05). Increased RUNX2 expression was associated with an upregulation in HIF-1 activation (p<0.05). More importantly, restoring miR-204 or decreasing RUNX2 expression decreases proliferation, resistance to apoptosis in human and experimental PAH model. Finally, in Sugen/hypoxia rat model of PAH, nebulization of either miR-204 mimic (n=10) or RUNX2 siRNA (n=10) improves significantly PAH (longitudinally assessed by cardiac Echo and invasively by closed chest right catheterization).
Conclusion: Taken together, our study uncovers a new miR-204-RUNX2 axis contributing to HIF-mediated pro-proliferative and anti-apoptotic phenotype in PAH. More experiments are required to explore the role of the miR-204/RUNX2 axis in BMP2/HDAC/P53 signaling, which are known to be regulated by RUNX2 in other cell types. This study might lead to the discovery of new potential therapeutic strategies for patients suffering of PAH.
- © 2013 by American Heart Association, Inc.