Implication of miR‐204/RUNX2‐dependent calcification pathway in pulmonary arterial hypertension (1089.23)

Abstract

Introduction: Pulmonary arterial hypertension (PAH) is a vascular remodeling disease characterized by occurrence of several vascular lesions. Interestingly, some biological pathways implicated in these lesions are also implicated in calcification processes. Nonetheless, the role for calcification lesions in PAH has never been explored. miR‐204, which is downregulated in PAH, is implicated in calcification processes by directly regulating the pro‐calcification transcription factor RUNX2. RUNX2 also regulates cell proliferation by activating HIF‐1. Thus, we hypothesized that miR‐204 downregulation in PAH triggers RUNX2 expression promoting calcification and vascular lesions in PAH. Methods and results: Using human explanted lungs, fresh distal pulmonary arteries (PAs) and freshly isolated pulmonary artery smooth muscle cells (PASMC) from both control and PAH patients, we demonstrated a significant downregulation of miR‐204 and an upregulation of RUNX2 in PAH compared to controls. The increase in RUNX2 in PAH patients was associated with an increase in distal PA calcification. Gain‐ and loss‐of‐function approaches in human PASMC showed that downregulation of miR‐204 in control PASMC increases RUNX2 expression, while increased miR‐204 in PAH‐PASMC decrease it. More importantly, restoring miR‐204 or decreasing RUNX2 expression in PAH‐PASMC decreases proliferation, resistance to apoptosis and alkaline phosphatase activity. Finally, in Sugen/hypoxia PAH rat model, nebulization of either miR‐204 mimic or RUNX2 siRNA significantly improves PAH.Conclusion: Taken together, our study uncovers a new miR‐204/RUNX2 axis contributing to both calcified lesions and vascular remodeling in distal PA of PAH patients. More experiments are required to further explore the role of RUNX2 in PAH pulmonary artery calcification. This study might lead to the discovery of new potential therapeutic strategies for patients suffering of PAH.