Abstract

Pulmonary hypertension (PH) associated with congenital heart disease is a progressive hemodynamic disease that can lead to increased pulmonary vascular resistance, vascular remodeling, and even right heart failure and death. LF3 is a novel inhibitor of the reporter gene activity of β-catenin/TCF4 interaction in the Wnt/β-catenin signal pathway. However, whether this action of LF3 can prevent PH development remains unclear. In this study, we investigated the therapeutic effect of LF3 in rat primary pulmonary artery smooth muscle cells (PASMCs) of the PH model. We found that LF3 inhibited the decrease in pulmonary artery acceleration time and ejection time by ultra-high-resolution ultrasound imaging and blocked the increase of pulmonary artery systolic pressure by using the BL420 biological function experimental system and right ventricular hypertrophy index by the electronic scales. Simultaneously, it prevented the increase of α-smooth muscle actin and fibronectin and the decrease of elastin in pulmonary arteries of rats in the PH group, as revealed by an immunohistochemical analysis. Moreover, cell proliferation and migration assays showed that LF3 significantly reduced the proliferation and migration of PASMCs. Western blotting and quantitative real-time polymerase chain reaction analyses revealed that LF3 suppressed the expression of proliferating cell nuclear antigens and Bcl-2 and increased the expression of Bax but did not alter the expressions of β-catenin and TCF4. Taken together, LF3 can reduce the migration and proliferation of PASMCs and induce their apoptosis to prevent the development of PH. It would be worthwhile to explore the potential use of LF3 in the treatment of PH.

中文翻译：

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小分子抑制剂LF3通过Wnt/β-catenin通路抑制肺动脉高压的发生

 抽象的

与先天性心脏病相关的肺动脉高压（PH）是一种进行性血流动力学疾病，可导致肺血管阻力增加、血管重塑，甚至右心衰竭和死亡。 LF3 是 Wnt/β-catenin 信号通路中 β-catenin/TCF4 相互作用的报告基因活性的新型抑制剂。然而，LF3 的这种作用是否可以阻止 PH 的发展仍不清楚。在本研究中，我们研究了 LF3 对 PH 模型大鼠原代肺动脉平滑肌细胞 (PASMC) 的治疗作用。我们通过超高分辨率超声成像发现，LF3抑制了肺动脉加速时间和射血时间的减少，通过BL420生物功能实验系统和电子秤显示的右心室肥厚指数，发现LF3抑制了肺动脉收缩压的增加。同时，免疫组织化学分析显示，它可以防止 PH 组大鼠肺动脉中 α-平滑肌肌动蛋白和纤连蛋白的增加以及弹性蛋白的减少。此外，细胞增殖和迁移测定表明，LF3显着降低PASMCs的增殖和迁移。蛋白质印迹和实时定量聚合酶链反应分析表明，LF3 抑制增殖细胞核抗原和 Bcl-2 的表达，增加 Bax 的表达，但不改变 β-catenin 和 TCF4 的表达。综上所述，LF3可以减少PASMCs的迁移和增殖并诱导其凋亡，从而预防PH的发展。探索 LF3 在治疗 PH 中的潜在用途是值得的。