Qinghai Provincial People 's Hospital Pharmacy Department, XiNing, China.
Department of Pharmacy, First Clinical Hospital of Lanzhou University, Lanzhou, China.
Pulm Pharmacol Ther. 2023 Oct;82:102229. doi: 10.1016/j.pupt.2023.102229. Epub 2023 Jun 22.
Hypoxic pulmonary hypertension (HPH) is a devastating disease worldwide; however, effective therapeutic drugs are lacking. This study investigated the effects and underlying mechanisms of LCZ696 treatment on hypoxia-induced pulmonary hypertension. Male Sprague-Dawley (SD) rats were kept in a hypobaric chamber with an oxygen concentration of 5% for 4 weeks. Rats were treated with either LCZ696 (18 mg/kg, 36 mg/kg, and 72 mg/kg) or sildenafil. The mean pulmonary artery pressure (mPAP), right ventricle hypertrophy index (RVHI), and lung system index were measured. Hematoxylin-eosin (HE) staining, Masson staining, and immunofluorescence staining were used for histological analysis. Enzyme linked immunosorbent assay (ELISA) kits were used to determine the concentrations of inflammatory and hypoxia-related factors. Western blotting was used to examine the expression of apoptotic and PI3K/AKT signaling pathway proteins in rat lung tissue. Hypoxia increased mPAP, RVHI, and lung system index and induced pulmonary vascular remodeling, pulmonary arteriomyosis, and pulmonary artery fibrosis. LCZ696 treatment reduced the increase in mPAP, RVHI, and the lung system index and ameliorated the induced pathological changes. Hypoxia upregulated expression of NF-kB, TNF-α, IL-6, HIF-1α, and Vascular endothelial growth factor (VEGF), decreased the ratio of Bax/Bcl-2, and activated the PI3K/AKT signaling pathway in lung tissue, and these effects were partially reversed by treatment with LCZ696. These results demonstrated that LCZ696 can ameliorate hypoxia-induced HPH by suppressing apoptosis, inhibiting the inflammatory response, and inhibiting the PI3K/AKT signaling pathway. It provides a reference for clinical rational drug use and lays a foundation for the study of HPH therapeutic drugs.
低氧性肺动脉高压（HPH）是一种全球性的破坏性疾病；然而，缺乏有效的治疗药物。本研究探讨了 LCZ696 治疗对低氧诱导的肺动脉高压的影响及其潜在机制。雄性 Sprague-Dawley（SD）大鼠在氧浓度为 5%的低压舱中饲养 4 周。大鼠分别用 LCZ696（18mg/kg、36mg/kg 和 72mg/kg）或西地那非治疗。测量平均肺动脉压（mPAP）、右心室肥厚指数（RVHI）和肺系统指数。进行苏木精-伊红（HE）染色、马松染色和免疫荧光染色进行组织学分析。酶联免疫吸附测定（ELISA）试剂盒用于测定炎症和低氧相关因子的浓度。Western blot 用于检测大鼠肺组织中凋亡和 PI3K/AKT 信号通路蛋白的表达。低氧增加了 mPAP、RVHI 和肺系统指数，并诱导了肺血管重构、肺小动脉肌病和肺动脉纤维化。LCZ696 治疗减轻了 mPAP、RVHI 和肺系统指数的增加，并改善了诱导的病理变化。低氧上调了 NF-kB、TNF-α、IL-6、HIF-1α 和血管内皮生长因子（VEGF）的表达，降低了 Bax/Bcl-2 比值，并激活了肺组织中的 PI3K/AKT 信号通路，这些作用部分被 LCZ696 治疗逆转。这些结果表明，LCZ696 可以通过抑制细胞凋亡、抑制炎症反应和抑制 PI3K/AKT 信号通路来改善低氧诱导的 HPH。为临床合理用药提供了参考，为 HPH 治疗药物的研究奠定了基础。
