Guo Xue-Wei, Zhang Hao, Huang Jia-Qi, Wang Si-Nian, Lu Yan, Cheng Bo, Dong Su-He, Wang Ying-Ying, Li Feng-Sheng, Li Yong-Wang
The Postgraduate Training Base of Jinzhou Medical University (The PLA Rocket Force Characteristic Medical Center), Beijing, China.
Department of Anesthesiology, The PLA Rocket Force Characteristic Medical Center, Beijing, China.
Front Mol Biosci. 2021 Sep 9;8:725274. doi: 10.3389/fmolb.2021.725274. eCollection 2021.
Pulmonary endothelial cell dysfunction plays an important role in ionizing radiation (IR)-induced lung injury. Whether pulmonary endothelial cell ferroptosis occurs after IR and what are the underlying mechanisms remain elusive. Here, we demonstrate that 15-Gy IR induced ferroptosis characterized by lethal accumulation of reactive oxygen species (ROS), lipid peroxidation, mitochondria shrinkage, and decreased glutathione peroxidase 4 (GPX4) and SLC7A11 expression in pulmonary endothelial cells. The phenomena could be mimicked by Yoda1, a specific activator of mechanosensitive calcium channel PIEZO1. PIEZO1 protein expression was upregulated by IR and . The increased PIEZO1 expression after IR was accompanied with increased calcium influx and increased calpain activity. The effects of radiation on lung endothelial cell ferroptosis was partly reversed by inhibition of PIEZO1 activity using the selective inhibitor GsMTx4 or inhibition of downstreaming Ca/calpain signaling using PD151746. Both IR and activation of PIEZO1 led to increased degradation of VE-cadherin, while PD151746 blocked these effects. VE-cadherin knockdown by specific siRNA causes ferroptosis-like phenomena with increased ROS and lipid peroxidation in the lung endothelial cells. Overexpression of VE-cadherin partly recused the ferroptosis caused by IR or PIEZO1 activation as supported by decreased ROS production, lipid peroxidation and mitochondria shrinkage compared to IR or PIEZO1 activation alone. In summary, our study reveals a previously unrecognized role of PIEZO1 in modulating ferroptosis, providing a new target for future mitigation of radiation-induced lung injury.
肺内皮细胞功能障碍在电离辐射（IR）诱导的肺损伤中起重要作用。IR后肺内皮细胞是否发生铁死亡及其潜在机制仍不清楚。在此，我们证明15 Gy的IR诱导肺内皮细胞发生铁死亡，其特征为活性氧（ROS）致命性积累、脂质过氧化、线粒体萎缩以及谷胱甘肽过氧化物酶4（GPX4）和溶质载体家族7成员11（SLC7A11）表达降低。机械敏感钙通道PIEZO1的特异性激活剂Yoda1可模拟这些现象。IR上调PIEZO1蛋白表达。IR后PIEZO1表达增加伴随着钙内流增加和钙蛋白酶活性增加。使用选择性抑制剂GsMTx4抑制PIEZO1活性或使用PD151746抑制下游Ca/钙蛋白酶信号传导可部分逆转辐射对肺内皮细胞铁死亡的影响。IR和PIEZO1激活均导致血管内皮钙黏蛋白（VE-cadherin）降解增加，而PD151746可阻断这些效应。通过特异性小干扰RNA（siRNA）敲低VE-cadherin会导致肺内皮细胞出现类似铁死亡的现象，ROS和脂质过氧化增加。与单独的IR或PIEZO1激活相比，VE-cadherin过表达部分挽救了由IR或PIEZO1激活引起的铁死亡，表现为ROS产生减少、脂质过氧化减少和线粒体萎缩。总之，我们的研究揭示了PIEZO1在调节铁死亡中以前未被认识的作用，为未来减轻辐射诱导的肺损伤提供了新靶点。
