本研究探讨了淮中1号地黄2-苯乙基-β-吡喃葡萄糖苷(Phe)对低氧性肺动脉高压(PH)的保护作用及其机制。旨在为PAH的临床治疗提供理论依据。雄性C57BL/6N小鼠随机分为正常组,模型组,阳性药物(波生坦,100mg·kg~(-1))组,低剂量和高剂量Phe组(20和40mg·kg〜(-1))。除了正常组,其他各组均在10%低氧环境中连续进行模型诱导5周,从第3周开始口服给药14天。心肺功能,右心室压,咳嗽和哮喘指数,肺损伤,细胞凋亡,氧化应激相关指标,免疫细胞,并检测磷脂酰肌醇3激酶(PI3K)/蛋白激酶B(Akt)/哺乳动物雷帕霉素靶蛋白(mTOR)/缺氧诱导因子1α(HIF-1α)通路相关蛋白或mRNA水平。此外,采用低氧诱导的肺动脉平滑肌细胞(PASMC),进一步探讨Phe干预PH联合PI3K前-nist(740Y-P)的机制。结果表明,Phe显著改善了PH小鼠的心肺功能,右心室压下降,咳嗽和哮喘指数,和肺损伤,减少细胞凋亡,氧化应激相关指标,和磷酸化Akt(p-Akt)和磷酸化mTOR(p-mTOR)的核水平,抑制HIF-1α和PI3KmRNA和蛋白的表达,并维持小鼠的免疫细胞稳态。进一步的机制研究表明,Phe显着降低了缺氧诱导的PASMC的活力和迁移能力,降低了HIF-1α和PI3K蛋白的表达以及p-Akt和p-mTOR的nuc-lear水平,这种效应被740Y-P阻断。因此,推测Phe可能通过减轻肺组织氧化应激和细胞凋亡的失衡以及调节免疫水平发挥抗PH作用,其机制可能与PI3K/Akt/mTOR/HIF-1α通路的调控有关。本研究有望为PH的治疗提供药物参考和研究思路。
The study investigated the protective effect and mechanism of 2-phenylethyl-beta-glucopyranoside(Phe) from Huaizhong No.1 Rehmannia glutinosa on hypoxic pulmonary hypertension(PH), aiming to provide a theoretical basis for clinical treatment of PAH. Male C57BL/6N mice were randomly divided into normal group, model group, positive drug(bosentan, 100 mg·kg~(-1)) group, and low-and high-dose Phe groups(20 and 40 mg·kg~(-1)). Except for the normal group, all other groups were continuously subjected to model induction in a 10% hypoxic environment for 5 weeks, with oral administration for 14 days starting from the 3rd week. The cardiopulmonary function, right ventricular pressure, cough and asthma index, lung injury, cell apoptosis, oxidative stress-related indicators, immune cells, and phosphatidylinositol 3-kinase(PI3K)/protein kinase B(Akt)/mammalian target of rapamycin(mTOR)/hypoxic inducible factor 1α(HIF-1α) pathway-related proteins or mRNA levels were examined. Furthermore, hypoxia-induced pulmonary arterial smooth muscle cell(PASMC) were used to further explore the mechanism of Phe intervention in PH combined with PI3K ago-nist(740Y-P). The results showed that Phe significantly improved the cardiopulmonary function of mice with PH, decreased right ventricular pressure, cough and asthma index, and lung injury, reduced cell apoptosis, oxidative stress-related indicators, and nuclear levels of phosphorylated Akt(p-Akt) and phosphorylated mTOR(p-mTOR), inhibited the expression levels of HIF-1α and PI3K mRNA and proteins, and maintained the immune cell homeostasis in mice. Further mechanistic studies revealed that Phe significantly reduced the viability and migration ability of hypoxia-induced PASMC, decreased the expression of HIF-1α and PI3K proteins and nuc-lear levels of p-Akt and p-mTOR, and this effect was blocked by 740Y-P. Therefore, it is inferred that Phe may exert anti-PH effects by alleviating the imbalance of oxidative stress and apoptosis in lung tissues and regulating immune levels, and its mechanism may be related to the regulation of the PI3K/Akt/mTOR/HIF-1α pathway. This study is expected to provide drug references and research ideas for the treatment of PH.