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NBL1 Mediates Endothelial-to-Mesenchymal Transition in Pulmonary Arterial Hypertension Related to Congenital Heart Disease.

Endothelial-to-mesenchymal transition (EndMT) plays a critical role in the flow-induced vascular remodeling process, such as pulmonary artery hypertension related to congenital heart disease (CHD-PAH). Neuroblastoma suppressor of tumorigenicity 1 (NBL1) is a secreted glycoprotein and has been implicated in CHD-PAH by aggravating the phenotypic transformation of smooth muscle cell (SMC). However, the underlying mechanisms regarding the interplay between NBL1 and endothelial cell (EC) in CHD-PAH remains to be fully elucidated. Thus, we aimed to identify the potential effect of NBL1 on EndMT by a novel flow-associated PAH model with Nbl1 knockout rats. The phenotype of EndMT was detected by RNA-seq and further examined by western blotting and immunostaining of pulmonary arteries. Our observation demonstrated that the novel strategy of Nbl1 knockout effectively attenuated flow-associated PAH through downregulation of EndMT to some extent. Mechanistic experiments were established on human pulmonary artery endothelial cells (HPAECs) to confirm that EndMT was induced by NBL1 in vitro. After 7 days stimulation with NBL1, levels of EndMT-related biomarkers and downstream transcription factors were quantified by RNA-seq, western blotting and immunocytochemistry. Both in vitro and in vivo experiments supported the imbalance of increased TGF-β and dysregulation of BMP signaling by NBL1. Blocking the canonical TGF-β pathway efficiently preserved endothelial function upon NBL1 stimulation. These data suggested that NBL1 aggravated flow-associated PAH by inducing EndMT via the TGF-β/BMP signaling pathway. Thus, antagonizing NBL1 and rebalancing TGF-β/BMP signaling may be a suitable therapeutic target for CHD-PAH.