State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
Beijing Key Laboratory of Drug Targets Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
Acta Pharmacol Sin. 2022 Sep;43(9):2325-2339. doi: 10.1038/s41401-022-00865-y. Epub 2022 Feb 21.
Pulmonary hypertension (PH) is a cardiopulmonary disease characterized by a progressive increase in pulmonary vascular resistance. One of the initial pathogenic factors of PH is pulmonary arterial remodeling under various stimuli. Current marketed drugs against PH mainly relieve symptoms without significant improvement in overall prognosis. Discovering and developing new therapeutic drugs that interfere with vascular remodeling is in urgent need. Puerarin is an isoflavone compound extracted from the root of Kudzu vine, which is widely used in the treatment of cardiovascular diseases. In the present study, we evaluated the efficacy of puerarin in the treatment of experimental PH. PH was induced in rats by a single injection of MCT (50 mg/kg, sc), and in mice by exposure to hypoxia (10% O) for 14 days. After MCT injection the rats were administered puerarin (10, 30, 100 mg · kg · d, i.g.) for 28 days, whereas hypoxia-treated mice were pre-administered puerarin (60 mg · kg · d, i.g.) for 7 days. We showed that puerarin administration exerted significant protective effects in both experimental PH rodent models, evidenced by significantly reduced right ventricular systolic pressure (RVSP) and lung injury, improved pulmonary artery blood flow as well as pulmonary vasodilation and contraction function, inhibited inflammatory responses in lung tissues, improved resistance to apoptosis and abnormal proliferation in lung tissues, attenuated right ventricular injury and remodeling, and maintained normal function of the right ventricle. We revealed that MCT and hypoxia treatment significantly downregulated BMPR2/Smad signaling in the lung tissues and PPARγ/PI3K/Akt signaling in the lung tissues and right ventricles, which were restored by puerarin administration. In addition, we showed that a novel crystal type V (Puer-V) exerted better therapeutic effects than the crude form of puerarin (Puer). Furthermore, Puer-V was more efficient than bosentan (a positive control drug) in alleviating the abnormal structural changes and dysfunction of lung tissues and right ventricles. In conclusion, this study provides experimental evidence for developing Puer-V as a novel therapeutic drug to treat PH.
肺动脉高压（PH）是一种以肺血管阻力进行性增加为特征的心肺疾病。PH 的最初致病因素之一是各种刺激下的肺动脉重构。目前市场上用于治疗 PH 的药物主要是缓解症状，对整体预后的改善作用不大。因此，迫切需要发现和开发新的能够干预血管重构的治疗药物。葛根素是从野葛根部提取的一种异黄酮化合物，广泛用于治疗心血管疾病。在本研究中，我们评估了葛根素治疗实验性 PH 的疗效。通过单次注射 MCT（50mg/kg，sc）诱导大鼠 PH，通过暴露于 10% O 2 14 天诱导小鼠 PH。MCT 注射后，大鼠给予葛根素（10、30、100mg·kg·d，ig）治疗 28 天，而缺氧处理的小鼠给予葛根素（60mg·kg·d，ig）治疗 7 天。我们发现，葛根素给药对两种实验性 PH 啮齿动物模型均具有显著的保护作用，表现为右心室收缩压（RVSP）和肺损伤显著降低，肺动脉血流以及肺血管舒张和收缩功能改善，肺组织炎症反应抑制，肺组织抗凋亡和异常增殖能力增强，右心室损伤和重构减轻，右心室功能正常。我们揭示 MCT 和缺氧处理显著下调肺组织中的 BMPR2/Smad 信号和肺组织及右心室中的 PPARγ/PI3K/Akt 信号，而葛根素给药可恢复这些信号。此外，我们还发现一种新型晶型 V（Puer-V）比葛根素的粗提物（Puer）具有更好的治疗效果。此外，Puer-V 在缓解肺组织和右心室异常结构改变和功能障碍方面比波生坦（阳性对照药物）更有效。综上所述，本研究为开发 Puer-V 作为治疗 PH 的新型治疗药物提供了实验依据。
