Abudukeremu Asimuguli, Aikemu Ainiwaer, Yang Tao, Fang Lei, Shanahati Daliya, Nijiati Yiliyaer
College of Pharmacy, Xinjiang Medical University, Urumqi, Xinjiang, 830011, China.
College of Pharmacy, Xinjiang Medical University, Urumqi, Xinjiang, 830011, China; College of Life Sciences, Xinjiang Normal University, Urumqi, 830017, China; Xinjiang Key Laboratory of Hetian Characteristic Chinese Traditional Medicine Research, Hetian, 848000, Xinjiang, China; Engineering Research Center for Quality Control of Uyghur Medicinal Materials and Preparations, Hetianm, 848000, Xinjiang Uyghur Autonomous Region, China.
Chem Biol Interact. 2025 Sep 5;418:111596. doi: 10.1016/j.cbi.2025.111596. Epub 2025 Jun 2.
Hypoxic pulmonary hypertension (HPH) is a chronic, progressive pulmonary vascular disease caused by prolonged exposure to low-oxygen conditions. Pulmonary vascular remodeling (PVR) is a key pathological feature of pulmonary artery hypertension (PAH), primarily driven by suppressed cell death and excessive proliferation of pulmonary artery smooth muscle cells (PASMCs). Current therapies for HPH primarily focus on vasodilation rather than directly targeting PVR, highlighting the need for treatments capable of reversing VR. Ferroptosis, a recently identified form of regulated cell death, has gained attention for its potential to eliminate cancer cells; however, its involvement in PVR remains unclear. We aimed to explore whether induction of ferroptosis could suppress abnormal PASMC proliferation and mitigate hypoxia-induced PVR. In the pulmonary artery, angiotensin-converting enzyme 2 (ACE2) promotes vasodilation and inhibits PASMC proliferation, suggesting a potential therapeutic target. This study demonstrated that the expression levels of ferroptosis-related proteins-glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11)- were significantly upregulated in lung tissues and PASMCs from hypoxia-induced Sugen5416/hypoxia (SuHx) mouse models, suggesting the presence of ferroptosis resistance. Notably, ACE2 activation induced ferroptosis, whereas reduced ACE2 activity led to resistance to ferroptosis. These findings suggest that enhanced ACE2 activity may inhibit abnormal PASMC proliferation and reverse hypoxia-induced PVR, as demonstrated by both in vivo and in vitro experiments. We hypothesize that modulation of ACE2 activity influences PVR through ferroptosis regulation. This study identifies potential therapeutic targets and new research directions for the pathogenesis and treatment of HPH.
缺氧性肺动脉高压（HPH）是一种由长期暴露于低氧环境引起的慢性进行性肺血管疾病。肺血管重塑（PVR）是肺动脉高压（PAH）的关键病理特征，主要由肺动脉平滑肌细胞（PASMCs）的细胞死亡抑制和过度增殖驱动。目前治疗HPH的方法主要集中在血管舒张，而非直接针对PVR，这凸显了对能够逆转血管重塑的治疗方法的需求。铁死亡是最近发现的一种程序性细胞死亡形式，因其消除癌细胞的潜力而受到关注；然而，其在PVR中的作用仍不清楚。我们旨在探讨诱导铁死亡是否能抑制PASMC异常增殖并减轻缺氧诱导的PVR。在肺动脉中，血管紧张素转换酶2（ACE2）促进血管舒张并抑制PASMC增殖，提示其可能是一个潜在的治疗靶点。本研究表明，在缺氧诱导的Sugen5416/缺氧（SuHx）小鼠模型的肺组织和PASMC中，铁死亡相关蛋白谷胱甘肽过氧化物酶4（GPX4）和溶质载体家族7成员11（SLC7A11）的表达水平显著上调，提示存在铁死亡抵抗。值得注意的是，ACE2激活诱导铁死亡，而ACE2活性降低导致对铁死亡的抵抗。体内和体外实验均表明，这些发现提示增强ACE2活性可能抑制PASMC异常增殖并逆转缺氧诱导的PVR。我们推测，ACE2活性的调节通过铁死亡调控影响PVR。本研究为HPH的发病机制和治疗确定了潜在的治疗靶点和新的研究方向。
