Department of Pharmacology, Shanxi Medical University, Taiyuan 030001, China.
Department of Pharmacology, Shanxi Medical University, Taiyuan 030001, China.
Life Sci. 2018 Aug 15;207:442-450. doi: 10.1016/j.lfs.2018.06.033. Epub 2018 Jun 30.
Endothelial-to-mesenchymal transition (EndoMT) was shown to lead to endothelial cell (EC) dysfunction in pulmonary arterial hypertension (PAH). Baicalein was reported to inhibit epithelial-to-mesenchymal transition (EMT), a biological process that has many regulatory pathways in common with EndoMT. Whether it can attenuate PAH by inhibiting EndoMT remains obscure.
PAH was induced by a single subcutaneous injection of MCT (60 mg/kg) in male Sprague Dawley rats. Two weeks after MCT administration, the rats in the treatment groups received baicalein orally (50 or 100 mg/kg/day) for an additional 2 weeks. Hemodynamic changes and right ventricular hypertrophy (RVH) were evaluated on day 28. Cardiopulmonary interstitial fibrosis was detected using Masson's trichrome, Picrosirius-red, and immunohistochemical staining. The reactivity of pulmonary arteries (PAs) was examined ex vivo. The protein expresson of EndoMT molecules, bone morphogenetic protein receptor 2 (BMPR2), and nuclear factor-κB (NF-κB) was examined to explore the mechanism of protective action of baicalein.
Baicalein (50 and 100 mg/kg) significantly alleviated MCT-induced PAH and cardiopulmonary interstitial fibrosis. Furthermore, baicalein treatment enhanced PA responsiveness to acetylcholine (ACh) in PAH rats. The upregulation of EndoMT molecules (N-cadherin, vimentin, Snail, and Slug) strongly suggest that EndoMT participates in MCT-induced PAH, which was reversed by baicalein (50 and 100 mg/kg) treatment. Moreover, baicalein partially reversed MCT-induced reductions in BMPR2 and NF-κB activation in the PAs.
Baicalein attenuated MCT-induced PAH in rats by inhibiting EndoMT partially via the NF-κB-BMPR2 pathway. Thus, baicalein might be considered as a promising treatment option for PAH.
已有研究表明，内皮-间充质转化（EndoMT）可导致肺动脉高压（PAH）中的内皮细胞（EC）功能障碍。白杨素已被报道可抑制上皮-间充质转化（EMT），这一生物学过程与 EndoMT 有许多共同的调控途径。然而，它是否可以通过抑制 EndoMT 来减轻 PAH 仍不清楚。
雄性 Sprague Dawley 大鼠通过单次皮下注射 MCT（60mg/kg）诱导 PAH。MCT 给药 2 周后，治疗组大鼠每天口服给予白杨素（50 或 100mg/kg），持续 2 周。第 28 天评估血流动力学变化和右心室肥厚（RVH）。使用 Masson 三色、苦味酸天狼猩红和免疫组织化学染色检测心肺间质纤维化。体外检测肺动脉（PA）的反应性。检测 EndoMT 分子、骨形态发生蛋白受体 2（BMPR2）和核因子-κB（NF-κB）的蛋白表达，以探讨白杨素的保护作用机制。
白杨素（50 和 100mg/kg）可显著缓解 MCT 诱导的 PAH 和心肺间质纤维化。此外，白杨素治疗增强了 PAH 大鼠 PA 对乙酰胆碱（ACh）的反应性。EndoMT 分子（N-钙黏蛋白、波形蛋白、Snail 和 Slug）的上调强烈表明，EndoMT 参与了 MCT 诱导的 PAH，而白杨素（50 和 100mg/kg）治疗可逆转这一现象。此外，白杨素部分逆转了 MCT 诱导的 PA 中 BMPR2 和 NF-κB 激活的降低。
白杨素通过 NF-κB-BMPR2 通路部分抑制 EndoMT，减轻 MCT 诱导的大鼠 PAH。因此，白杨素可能被视为一种有前途的 PAH 治疗选择。
