Original articleLEF-1 gene silencing inhibits pulmonary vascular remodeling and occurrence of pulmonary arterial hypertension through the β-catenin signaling pathway

Add time:08/24/2019    Source:sciencedirect.com

Pulmonary arterial hypertension (PAH) has been known to result in progressive pulmonary artery pressures (PAP), pulmonary vascular resistance, and right ventricular failure. Emerging evidence has highlighted the function lymphoid enhancer-binding factor 1 (LEF-1) exerts in human diseases along with its potential participation in PAH. Herein, the present study aims to investigate the mechanisms by which LEF-1 affects the pulmonary vascular remodeling in rat models of PAH via the β-catenin signaling pathway. Both pulmonary vascular remodeling and PAP in the rat pulmonary arterioles were observed by using blood gas analysis as well as plasma NO level detection. Cells from the rats were then treated using monocrotaline (MCT) with PM2.5 also being treated with either shLEF-1, HU-308 (agonist of β-catenin signaling pathway) or shLEF-1 + HU-308. Expressions of the following: LEF-1, GSK-3β, β-catenin, PCNA, Caspase-3, survivin, and Bax were all determined by employing both RT-qPCR and Western blot. Cell proliferation, senescence, and apoptosis calculations were all measured by using the CCK-8 assay, SA β-Gal and flow cytometry methods, respectively. Rats that were treated with the combination of MCT + PM2.5, afterwards presented with a noticeably higher degree of pulmonary vascular remodeling and PAP, and reduced plasma levels of NO; besides, the expressions of LEF-1, GSK-3β, β-catenin, PCNA, and survivin were all elevated, while the expressions of both Caspase-3 and Bax were reduced. Following treatment of HU-308, cell senescence, and apoptosis were all inhibited, while cell proliferation had been contrarily enhanced; the transfection of shLEF-1. reversed the tendency. These results suggested demonstrate that LEF-1 gene silencing inhibited the activation of β-catenin signaling pathway, thereby suppressing both the occurrence and pulmonary vascular remodeling of PAH. Therefore, LEF-1 gene silencing may become a novel target for PAH treatment.

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