Leukotriene B4 induces proliferation of rat pulmonary arterial smooth muscle cells via modulating GSK-3β/β-catenin pathway
Leukotriene B4 induces proliferation of rat pulmonary arterial smooth muscle cells via modulating GSK-3β/β-catenin pathway
复制标题
白三烯 B-4 通过调节 GSK-3 β/β-catenin 通路诱导大鼠肺动脉平滑肌细胞增殖
DOI：
10.1016/j.ejphar.2019.172823
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发表时间：
2020-01-15
影响因子：
5
通讯作者：
Li, Manxiang
中科院分区：
文献类型：
--
作者：
Li, Shaojun;Zhai, Cui;Li, Manxiang
白三烯B 4（LTB 4）参与肺动脉平滑肌细胞（PASMC）增殖和肺动脉重构，从而导致肺动脉高压（PAH）的发生。然而，潜在的分子机制仍然知之甚少。本研究报告旨在解决这一问题。我们的研究结果表明，LTB4剂量和时间依赖性地诱导原代培养的大鼠PASMCs增殖，这伴随着磷脂酰肌醇-3-激酶/Akt的激活（PI3K/Akt）和细胞外信号调节激酶1/2（ERK 1/2）信号通路，以及随后的糖原合成酶激酶-3 β（GSK-3 β）失活、β-连环蛋白上调和细胞周期蛋白D1表达诱导。PI3K抑制剂（LY294002）或MEK抑制剂（U0126）的存在或预先用siRNA沉默β-catenin抑制LTB4诱导的cyclin D1上调和PASMCs增殖。此外，GSK-3 β的失活或缺失可上调PASMCs中的β-catenin和cyclin D1。总之，我们的研究表明，PI3K/Akt和ERK 1/2通路的激活通过调节GSK-3 β/β-catenin/cyclin D1轴介导LTB4诱导的PASMCs增殖，并表明靶向该通路可能具有缓解血管重塑和有益于PAH的潜在价值。
Leukotriene B-4 (LTB4) has been found to contribute to pulmonary arterial smooth muscle cells (PASMCs) proliferation and pulmonary arterial remodeling therefore the development of pulmonary arterial hypertension (PAH). Yet, the underlying molecular mechanisms remain poorly understood. The present study aims to address this issue. Our results demonstrate that LTB4 dose- and time-dependently induced proliferation of primary cultured rat PASMCs, this was accompanied with the activation of phosphatidylinositol-3-kinase/Akt (PI3K/Akt) and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathways, and consequent inactivation of glycogen synthase kinase-3 beta (GSK-3 beta), up-regulation of beta-catenin and induction of cyclin D1 expression. The presence of PI3K inhibitor (LY294002) or MEK inhibitor (U0126) or prior silencing of beta-catenin with siRNA suppressed LTB4-induced cyclin D1 up-regulation and PASMCs proliferation. In addition, inactivation or lack of GSK-3 beta up-regulated beta-catenin and cyclin D1 in PASMCs. Taken together, our study indicates that activation of PI3K/Akt and ERK1/2 pathways mediates LTB4-induced PASMCs proliferation by modulating GSK-3 beta/beta-catenin/cyclin D1 axis and suggests that targeting this pathway might have potential value in alleviating vascular remodeling and benefit PAH.