Nie Xinran, Wu Zhuhua, Shang Junyi, Zhu Li, Liu Yingli, Qi Yong
Department of Pulmonary and Critical Care Medicine, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, Henan, China; Academy of Medical Science, Zhengzhou University, Zhengzhou, Henan, China.
Department of Pulmonary and Critical Care Medicine, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, Henan, China.
Eur J Pharmacol. 2023 Mar 15;943:175546. doi: 10.1016/j.ejphar.2023.175546. Epub 2023 Jan 25.
Endothelial dysfunction is essential in pulmonary arterial hypertension (PAH) pathogenesis and is considered to be a therapeutic target of PAH. Curcumol is a bioactive sesquiterpenoid with pharmacological properties including restoring endothelial cells damage. This study aimed to evaluate the effect of curcumol on PAH rats and investigate its possible mechanisms. PAH was induced by subcutaneous injection of 60 mg/kg monocrotaline (MCT) in male Sprague Dawley rats. Curcumol (12.5, 25, and 50 mg/kg/day) were administered by intragastric administration for 3 weeks. The results demonstrated that curcumol dose-dependently alleviated MCT-induced right ventricular hypertrophy and pulmonary arterial wall thickness. In addition, endothelial-to-mesenchymal transition (EndMT) in the pulmonary arteries of MCT-challenged rats was inhibited after curcumol treatment, as evidenced by the restored expressions of endothelial and myofibroblast markers. The possible pharmacological mechanisms of curcumol were analyzed using network pharmacology. After screening the common therapeutic targets of PAH and curcumol by searching related databases and comparison, pathway enrichment was performed and AKT/GSK3β was screened out as a possible signaling pathway which was relevant to the therapeutic mechanism of curcumol on PAH. Western blot analysis verified this in lung tissues. Moreover, combination of TNF-α, TGF-β1 and IL-1β-induced EndMT in primary rat pulmonary arterial endothelial cells were blocked by curcumol, and this effect was resembled by PI3K/AKT inhibitor LY294002. Above all, our study suggested that curcumol inhibited EndMT via inhibiting the AKT/GSK3β signaling pathway, which may contribute to its alleviated effect on PAH. Curcumol may be developed as a therapeutic for PAH in the future.
内皮功能障碍在肺动脉高压（PAH）发病机制中至关重要，被认为是PAH的一个治疗靶点。莪术醇是一种具有生物活性的倍半萜类化合物，具有包括修复内皮细胞损伤在内的药理特性。本研究旨在评估莪术醇对PAH大鼠的影响，并探讨其可能的作用机制。通过皮下注射60mg/kg的野百合碱（MCT）诱导雄性Sprague Dawley大鼠发生PAH。莪术醇（12.5、25和50mg/kg/天）通过灌胃给药3周。结果表明，莪术醇剂量依赖性地减轻了MCT诱导的右心室肥厚和肺动脉壁厚度。此外，莪术醇治疗后，MCT攻击大鼠肺动脉中的内皮-间充质转化（EndMT）受到抑制，这通过内皮和成肌纤维细胞标志物表达的恢复得以证明。使用网络药理学分析了莪术醇可能的药理机制。通过检索相关数据库并比较筛选出PAH和莪术醇的共同治疗靶点后，进行了通路富集分析，筛选出AKT/GSK3β作为与莪术醇治疗PAH机制相关的可能信号通路。蛋白质免疫印迹分析在肺组织中证实了这一点。此外，莪术醇阻断了肿瘤坏死因子-α、转化生长因子-β1和白细胞介素-1β诱导的原代大鼠肺动脉内皮细胞中的EndMT，PI3K/AKT抑制剂LY294002也有类似作用。综上所述，我们的研究表明，莪术醇通过抑制AKT/GSK3β信号通路抑制EndMT，这可能有助于其对PAH的缓解作用。莪术醇未来可能被开发为PAH的一种治疗药物。
