College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China.
State Key Laboratory of Respiratory Disease, Guangdong Key Laboratory of Vascular Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
Oxid Med Cell Longev. 2022 Jun 17;2022:2782429. doi: 10.1155/2022/2782429. eCollection 2022.
Pulmonary arterial hypertension (PAH) is a complex pulmonary vasculature disease characterized by progressive obliteration of small pulmonary arteries and persistent increase in pulmonary vascular resistance, resulting in right heart failure and death if left untreated. Artemisinin (ARS) and its derivatives, which are common antimalarial drugs, have been found to possess a broad range of biological effects. Here, we sought to determine the therapeutic benefit and mechanism of ARS and its derivatives treatment in experimental pulmonary hypertension (PH) models.
Isolated perfused/ventilated lung and isometric tension measurements in arteries were performed to test pulmonary vasoconstriction and relaxation. Monocrotaline (MCT) and hypoxia+Su5416 (SuHx) were administered to rats to induce severe PH. Evaluation methods of ARS treatment and its derivatives in animal models include echocardiography, hemodynamics measurement, and histological staining. , the effect of these drugs on proliferation, viability, and hypoxia-inducible factor 1 (HIF1) was examined in human pulmonary arterial smooth muscle cells (hPASMCs).
ARS treatment attenuated pulmonary vasoconstriction induced by high K solution or alveolar hypoxia, decreased pulmonary artery (PA) basal vascular tension, improved acetylcholine- (ACh-) induced endothelial-dependent relaxation, increased endothelial nitric oxide (NO) synthase (eNOS) activity and NO levels, and decreased levels of NAD(P)H oxidase subunits (NOX2 and NOX4) expression, NAD(P)H oxidase activity, and reactive oxygen species (ROS) levels of pulmonary arteries (PAs) in MCT-PH rats. NOS inhibitor, L-NAME, abrogated the effects of ARS on PA constriction and relaxation. Furthermore, chronic application of both ARS and its derivative dihydroartemisinin (DHA) attenuated right ventricular systolic pressure (RVSP), Fulton index (right ventricular hypertrophy), and vascular remodeling of PAs in the two rat PH models. In addition, DHA inhibited proliferation and migration of hypoxia-induced PASMCs.
In conclusion, these results indicate that treatment with ARS or DHA can inhibit PA vasoconstriction, PASMC proliferation and migration, and vascular remodeling, as well as improve PA endothelium-dependent relaxation, and eventually attenuate the development and progression of PH. These effects might be achieved by decreasing NAD(P)H oxidase generated ROS production and increasing eNOS activation to release NO in PAs. ARS and its derivatives might have the potential to be novel drugs for the treatment of PH.
肺动脉高压（PAH）是一种复杂的肺血管疾病，其特征为小肺动脉进行性闭塞和肺血管阻力持续增加，如果不治疗，会导致右心衰竭和死亡。青蒿素（ARS）及其衍生物是常见的抗疟药物，已被发现具有广泛的生物学效应。在这里，我们旨在确定 ARS 及其衍生物在实验性肺动脉高压（PH）模型中的治疗益处和机制。
进行离体灌流/通气肺和血管等长张力测量，以测试肺血管收缩和舒张。给予野百合碱（MCT）和缺氧+Su5416（SuHx）以诱导严重 PH。ARS 治疗及其衍生物在动物模型中的评估方法包括超声心动图、血流动力学测量和组织学染色。此外，还在人肺动脉平滑肌细胞（hPASMCs）中检查了这些药物对增殖、活力和缺氧诱导因子 1（HIF1）的影响。
ARS 治疗减轻了高 K 溶液或肺泡缺氧引起的肺血管收缩，降低了肺动脉（PA）基础血管张力，改善了乙酰胆碱-（ACh-）诱导的内皮依赖性舒张，增加了内皮一氧化氮合酶（eNOS）活性和一氧化氮（NO）水平，降低了 NAD（P）H 氧化酶亚基（NOX2 和 NOX4）表达、NAD（P）H 氧化酶活性和活性氧（ROS）水平。NOS 抑制剂 L-NAME 阻断了 ARS 对 PA 收缩和舒张的作用。此外，ARS 和其衍生物二氢青蒿素（DHA）的慢性应用减轻了两种大鼠 PH 模型的右心室收缩压（RVSP）、富尔顿指数（右心室肥厚）和 PA 血管重塑。此外，DHA 抑制了缺氧诱导的 PASMC 增殖和迁移。
总之，这些结果表明，ARS 或 DHA 的治疗可抑制 PA 血管收缩、PASMC 增殖和迁移以及血管重塑，并改善 PA 内皮依赖性舒张，最终减轻 PH 的发生和进展。这些作用可能是通过减少 NAD（P）H 氧化酶产生的 ROS 产生和增加 eNOS 激活以释放 PA 中的 NO 来实现的。ARS 及其衍生物可能具有成为 PH 治疗新药物的潜力。
