miR-29 inhibits endothelial-to-mesenchymal transition in pulmonary hypertension of the newborn by regulating LRP6.

Pulmonary hypertension of the newborn (PHN) is a common pulmonary vascular disease in newborns, affecting the prognosis of affected infants and even leading to death. Currently, there is still no specific targeted prevention and treatment program available. In recent years, research on the regulatory mechanism of endothelial-to-mesenchymal transition (EndMT) has become a hot topic, with the interplay between miRNAs and the Wnt signaling pathway playing an important role. MiR-29 is highly expressed in distal pulmonary arteriolar smooth muscle cells and endothelial cells. In miR-29 gene knockout mice, pathological changes in lung tissue can be observed, indicating an obstruction in the maturation of smooth muscle cells in the distal pulmonary arterioles. LRP6 is an important Wnt co-receptor in the Wnt signaling pathway, and the Targetscan website predicts a binding site between miR-29 and LRP6. Therefore, our studies establish a role for decreased miR29a in the endothelial mesenchymal transition through activation of the LRP6-Wnt signaling pathway in neonatal hypoxia-mediated PAH. By generating hypoxic newborn rat models of pulmonary artery hypertension and hypoxic injury models of pulmonary vascular endothelial cells, we observed the presence of EndMT in the model group, as well as the activation of the LRP6 and Wnt/β-catenin signaling pathways and the differential expression of the miR-29 family, particularly miR-29a. Subsequently, We used cell transfection technology to overexpress/knock down miR-29a and LRP6, respectively, to observe changes in EndMT-related indicators and successfully found that miR-29a and LRP6 can negatively and positively regulate the occurrence of EndMT, respectively. Finally, the dual-luciferase reporter gene assay confirmed that LRP6 can directly bind to miR-29a-3p. These findings provide experimental evidence of the potential of miR-29 as a novel target for the prevention and treatment of PHN.