Department of Respiratory Medicine, The Fourth Affiliated Hospital of Kunming Medical University, The Second People's Hospital of Yunnan Province, Kunming, 650021, Yunnan, China.
College of Pharmacy, Kunming Medical University, Kunming, 650500, Yunnan, China.
Eur J Pharmacol. 2019 Jul 15;855:227-234. doi: 10.1016/j.ejphar.2019.05.021. Epub 2019 May 11.
Phosphatase and tensin homolog (PTEN) plays an important role in the pathogenesis of hypoxic pulmonary hypertension (HPH). A decrease in PTEN expression is associated with the hypermethylation of its promoter. However, whether the demethylation of the PTEN gene could attenuate HPH remains unknown. 5-Aza-2'-deoxycytidine (5-Aza-dC) is a DNA methyltransferase (DNMT) inhibitor. The present study was designed to investigate the effects and mechanisms of 5-Aza-dC on HPH. The proliferation, migration and apoptosis of rat pulmonary artery smooth muscle cells (PASMCs) induced by hypoxia and treated with 5-Aza-dC were detected. The expression of PTEN and DNMTs and the PTEN methylation status of PASMCs were detected. SD rats were randomly divided into normal group, hypoxia group and hypoxia + 5-Aza-dC group. The expression of PTEN was decreased, the expression of DNMTs was increased, and the methylation status of PTEN was increased in hypoxia-induced PASMCs. However, 5-Aza-dC can rescue the decreased PTEN, inhibit DNMT levels in a dose-dependent manner and suppress PTEN methylation. Furthermore, the demethylation of PTEN, which was induced by 5-Aza-dC, inhibited the proliferation, migration and promoted apoptosis in PASMCs. In vivo studies further demonstrated that the expression of PTEN, mean pulmonary artery pressure and right ventricular hypertrophy index in HPH rats was attenuated by 5-Aza-dC. 5-Aza-dC also suppressed the expression of DNMTs and PTEN methylation in the lungs of HPH rats. These results indicated that PTEN promoter methylation status is involved in HPH. 5-Aza-dC, as a DNMT inhibitor, has the potential to attenuate HPH via demethylation of the PTEN promoter.
磷酸酶和张力蛋白同源物（PTEN）在低氧性肺动脉高压（HPH）的发病机制中发挥重要作用。PTEN 表达的减少与启动子的高甲基化有关。然而，PTEN 基因的去甲基化是否能减轻 HPH 尚不清楚。5-氮杂-2′-脱氧胞苷（5-Aza-dC）是一种 DNA 甲基转移酶（DNMT）抑制剂。本研究旨在探讨 5-Aza-dC 对 HPH 的影响及其机制。检测低氧诱导的大鼠肺动脉平滑肌细胞（PASMCs）增殖、迁移和凋亡以及用 5-Aza-dC 处理后的 PTEN 和 DNMTs 表达和 PASMCs 的 PTEN 甲基化状态。SD 大鼠随机分为正常组、低氧组和低氧+5-Aza-dC 组。结果显示，低氧诱导的 PASMCs 中 PTEN 表达降低，DNMTs 表达增加，PTEN 甲基化状态增加。然而，5-Aza-dC 可挽救 PTEN 的降低，呈剂量依赖性抑制 DNMT 水平并抑制 PTEN 甲基化。此外，5-Aza-dC 诱导的 PTEN 去甲基化抑制 PASMCs 的增殖、迁移并促进其凋亡。体内研究进一步表明，5-Aza-dC 可减轻 HPH 大鼠的 PTEN 表达、平均肺动脉压和右心室肥厚指数，并抑制 HPH 大鼠肺部的 DNMTs 表达和 PTEN 甲基化。这些结果表明，PTEN 启动子甲基化状态参与 HPH。5-Aza-dC 作为一种 DNMT 抑制剂，通过 PTEN 启动子的去甲基化具有减轻 HPH 的潜力。
