Outpatient department, Urumqi Youai Hospital, Xinjiang Uygur Autonomous Region, Urumqi, 830063, China.
Department of Critical Care Medicine, Urumqi Youai Hospital, Urumqi, 830063, Xinjiang Uygur Autonomous Region, China.
BMC Pulm Med. 2023 Oct 12;23(1):386. doi: 10.1186/s12890-023-02660-9.
Astragaloside (AS)-IV, extracted from traditional Chinese medicine Astragalus mongholicus, has been widely used in the anti-inflammatory treatment for cardiovascular disease. However, the mechanism by which AS-IV affects pulmonary artery hypertension (PAH) development remains largely unknown.
Monocrotaline (MCT)-induced PAH model rats were administered with AS-IV, and hematoxylin-eosin staining and Masson staining were performed to evaluate the histological change in pulmonary tissues of rats. Pulmonary artery smooth muscle cells (PASMCs) were treated by hypoxia and AS-IV. Pyroptosis and fibrosis were assessed by immunofluorescence, western blot and enzyme-linked immunosorbent assay.
AS-IV treatment alleviated pulmonary artery structural remodeling and pulmonary hypertension progression induced by MCT in rats. AS-IV suppressed the expression of pyroptosis-related markers, the release of pro-inflammatory cytokine interleukin (IL)-1β and IL-18 and fibrosis development in pulmonary tissues of PAH rats and in hypoxic PAMSCs. Interestingly, the expression of prolyl-4-hydroxylase 2 (PHD2) was restored by AS-IV administration in PAH model in vivo and in vitro, while hypoxia inducible factor 1α (HIF1α) was restrained by AS-IV. Mechanistically, silencing PHD2 reversed the inhibitory effect of AS-IV on pyroptosis, fibrosis trend and pyroptotic necrosis in hypoxia-cultured PASMCs, while the HIF1α inhibitor could prevent these PAH-like phenomena.
Collectively, AS-IV elevates PHD2 expression to alleviate pyroptosis and fibrosis development during PAH through downregulating HIF1α. These findings may provide a better understanding of AS-IV preventing PAH, and the PHD2/HIF1α axis may be a potential anti-pyroptosis target during PAH.
从中药黄芪中提取的黄芪甲苷（AS-IV）已广泛用于心血管疾病的抗炎治疗。然而，AS-IV 影响肺动脉高压（PAH）发展的机制在很大程度上尚不清楚。
用 AS-IV 处理野百合碱（MCT）诱导的 PAH 模型大鼠，进行苏木精-伊红染色和 Masson 染色，评估大鼠肺组织的组织学变化。用缺氧和 AS-IV 处理肺动脉平滑肌细胞（PASMCs）。通过免疫荧光、western blot 和酶联免疫吸附试验评估细胞焦亡和纤维化。
AS-IV 治疗减轻了 MCT 诱导的大鼠肺动脉结构重塑和肺动脉高压进展。AS-IV 抑制了 PAH 大鼠肺组织和缺氧 PASMCs 中细胞焦亡相关标志物的表达、促炎细胞因子白细胞介素（IL）-1β和 IL-18 的释放以及纤维化的发展。有趣的是，AS-IV 给药在体内和体外均恢复了 PAH 模型中脯氨酰-4-羟化酶 2（PHD2）的表达，同时抑制了缺氧诱导因子 1α（HIF1α）。机制上，沉默 PHD2 逆转了 AS-IV 对缺氧培养的 PASMCs 中细胞焦亡、纤维化趋势和焦亡性坏死的抑制作用，而 HIF1α 抑制剂可以阻止这些类似 PAH 的现象。
总之，AS-IV 通过下调 HIF1α来提高 PHD2 的表达，从而减轻 PAH 中的细胞焦亡和纤维化发展。这些发现可能为更好地理解 AS-IV 预防 PAH 提供依据，并且 PHD2/HIF1α 轴可能是 PAH 期间潜在的抗细胞焦亡靶点。
