Objectives: Pulmonary arterial hypertension (PAH) is a fatal disease which is characterized by pulmonary artery endothelial cell (PAEC) dysfunction and occlusive vascular remodeling. Activated bone morphogenetic protein type 2 receptor… Click to show full abstract
Objectives: Pulmonary arterial hypertension (PAH) is a fatal disease which is characterized by pulmonary artery endothelial cell (PAEC) dysfunction and occlusive vascular remodeling. Activated bone morphogenetic protein type 2 receptor (BMPR2) signaling plays a key role in maintaining PAECs function, but its downstream regulatory mechanism is still elusive. Adenosine deaminase acting on RNA 1 (ADAR1), an important RNA-editing enzyme, recently intrigued our interest for its essential role in vascular remodeling diseases. Here we hypothesized that ADAR1, as a downstream factor of BMPR2 signaling, regulates PAEC function and PAH progression. Methods: In vivo, we performed the monocrotaline (MCT) injection to injury BMPR2 singnaling and create experimental PAH rat model, so as to assess the impact of BMPR2 on ADAR1 protein and mRNA expression. In vitro model, we interfered BMPR2 signaling to investigate its role on ADAR1 expression in human PAECs. Results: In PAH rat model, we demonstrated that loss of BMPR2 signaling is associated with increased ADAR1 gene and protein expression. And these findings could be reproduced in vitro PAECs treated with BMPR2 siRNA. Moreover, when PAECs deficient in BMPR2 signaling was stimulated with tumor necrosis factor &agr; (TNF-&agr;), an increase of ADAR1 expression was observed and related to enhanced messenger RNA (mRNA) translation. Additionally, administration of BMP9, acts as an activator of BMPR2 signaling, ADAR1 expression is reversed in PAECs. Finally, knockdown of ADAR1 expression alleviated the dysfunction of PAECs that is characterized as less apoptotic cell and decreased ability of migration. Conclusion : This study reveals that ADAR1 is a critical downstream effector of BMPR2 signaling in PAECs to promote PAH.
               
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