Geng Yumei, Wang Huijie, Bai Zhenzhong, Ge Rili
Research Center for High Altitude Medicine, Qinghai University, Xining 810001, China.
Key Laboratory of High Altitude Medicine (Ministry of Education), Qinghai University, Xining 810001, China.
Biomolecules. 2025 May 21;15(5):742. doi: 10.3390/biom15050742.
Iron deficiency is highly prevalent in patients with idiopathic pulmonary hypertension; nevertheless, its role and clinical significance in hypoxic pulmonary hypertension (HPH) remain elusive. Therefore, this study aims to clarify the role and molecular mechanisms of iron in HPH. By means of a retrospective analysis of clinical data from HPH patients and examinations of HPH animal models, we discovered that both HPH patients and animal models exhibit significant iron deficiency, characterized by reduced hepatic iron storage and elevated hepcidin expression. To further explore iron's role in HPH, we modulated iron metabolism through pharmacological and dietary interventions in chronic hypoxic animal models. The results showed that iron deficiency exacerbated chronic hypoxia-induced pulmonary hypertension and right ventricular hypertrophy, while iron supplementation alleviated these conditions. Further investigations revealed that iron regulates HIF2α expression in pulmonary arterial endothelial cells (PAECs) under chronic hypoxia. Therefore, through in vivo and in vitro experiments, we demonstrated that HIF2α inhibition attenuates chronic hypoxia-induced pulmonary hypertension and right ventricular hypertrophy. Mechanistically, chronic hypoxia-mediated iron deficiency enhances HIF2α activation, subsequently suppressing iron/sulfur cluster assembly enzyme (ISCU) expression. This leads to decreased mitochondrial complexes I and III activity, increased reactive oxygen species (ROS) production, and inhibited oxidative phosphorylation. Consequently, metabolic reprogramming in PAECs results in a proliferation/apoptosis imbalance, ultimately exacerbating hypoxia-induced pulmonary hypertension and right ventricular hypertrophy. Collectively, our findings demonstrate that iron supplementation mitigates HPH progression by modulating HIF2α-mediated metabolic reprogramming in PAECs, revealing multiple therapeutic targets for HPH.
缺铁在特发性肺动脉高压患者中极为普遍；然而，其在低氧性肺动脉高压（HPH）中的作用和临床意义仍不明确。因此，本研究旨在阐明铁在HPH中的作用及分子机制。通过对HPH患者临床数据的回顾性分析以及对HPH动物模型的检测，我们发现HPH患者和动物模型均表现出明显的缺铁，其特征为肝脏铁储存减少和铁调素表达升高。为进一步探究铁在HPH中的作用，我们通过对慢性低氧动物模型进行药理学和饮食干预来调节铁代谢。结果表明，缺铁加剧了慢性低氧诱导的肺动脉高压和右心室肥厚，而补充铁则缓解了这些情况。进一步研究发现，铁在慢性低氧条件下调节肺动脉内皮细胞（PAECs）中HIF2α的表达。因此，通过体内和体外实验，我们证明抑制HIF2α可减轻慢性低氧诱导的肺动脉高压和右心室肥厚。机制上，慢性低氧介导的缺铁增强了HIF2α的激活，随后抑制铁硫簇组装酶（ISCU）的表达。这导致线粒体复合物I和III的活性降低，活性氧（ROS）生成增加，氧化磷酸化受到抑制。因此，PAECs中的代谢重编程导致增殖/凋亡失衡，最终加剧低氧诱导的肺动脉高压和右心室肥厚。总的来说，我们的研究结果表明，补充铁可通过调节PAECs中HIF2α介导的代谢重编程来减轻HPH的进展，揭示了HPH的多个治疗靶点。
