内质网应激诱导的内皮细胞热解通过IRE1α/SCaspase-3/GSDME通路促进肺血管重塑和肺动脉高压
Endoplasmic Reticulum Stress-Induced Endothelial Cell Pyroptosis Contributes to Pulmonary Vascular Remodeling and Pulmonary Arterial Hypertension via IRE1α/Caspase-3/GSDME Pathway.
摘要(中文译文)
内皮细胞（EC）损伤被认为是肺动脉高压（PAH）的起始触发因素。过度的内质网（ER）应激可导致内皮细胞早期损伤并继发细胞死亡。焦亡导致内皮细胞损伤并加速PAH进展。然而，内质网应激是否以及如何调控内皮细胞焦亡，尤其是在PAH进展中的作用，仍不清楚。本研究在PAH模型肺组织中评估了内质网应激和内皮细胞焦亡的激活水平。分别采用药理学抑制剂、小干扰RNA和特异性抑制剂在体内和体外探讨内质网应激调控PAH中内皮细胞焦亡的作用及机制。在野百合碱诱导的PAH大鼠早期阶段，内质网应激和内皮细胞焦亡即被激活。抑制内质网应激可抑制PAH大鼠内皮细胞GSDME（gasdermin E）的激活。持续且严重的内质网应激增加内皮细胞中GSDME-NT（gasdermin E N端）水平和LDH（乳酸脱氢酶）释放。沉默GSDME或caspase-3可逆转内质网应激诱导的内皮细胞焦亡效应。机制上，IRE1α（肌醇需求激酶1α）激酶活性介导了内质网应激触发的caspase-3/GSDME激活。通过KIRA6（IRE1α激酶抑制剂）处理抑制IRE1α激酶活性，可通过抑制caspase-3/GSDME介导的内皮细胞焦亡及随后的内皮完整性破坏，减轻PAH的发展。这些结果表明，持续且未缓解的内质网应激诱导的IRE1α激活在调控内皮细胞焦亡中发挥关键作用，导致早期内皮细胞损伤并加速PAH进展。
Abstract
Endothelial cell (EC) injury is regarded as the initiating trigger of pulmonary arterial hypertension (PAH). Excessive endoplasmic reticulum (ER) stress could cause early damage to ECs with subsequent cell death. Pyroptosis leads to EC damage and accelerates PAH progression. However, whether and how ER stress plays a role in regulating EC pyroptosis, especially in PAH progression, remains unclear. The activation level of ER stress and endothelial pyroptosis were assessed in the lungs of a PAH model. Pharmacological inhibitors, small-interfering RNA, and specific inhibitors were used to explore the role and the mechanism of ER stress in regulating EC pyroptosis in PAH in vivo and in vitro, respectively. ER stress and endothelial pyroptosis were activated in the early stage of monocrotaline-induced PAH rats. Inhibition of ER stress suppressed the activation of the endothelial GSDME (gasdermin E) in PAH rats. Prolonged and severe ER stress increased the level of the GSDME-NT (N-terminal of gasdermin E) and LDH (lactic dehydrogenase) release in ECs. Silencing GSDME or caspase-3 reversed the effect of ER stress-induced EC pyroptosis. Mechanistically, the IRE1α (inositol-requiring kinase 1α) kinase activity mediated the activation of ER stress-triggered caspase-3/GSDME. Inhibition of the IRE1α kinase activity by KIRA6 (IRE1α kinase inhibitor) treatment alleviated the development of PAH by inhibiting caspase-3/GSDME-mediated endothelial pyroptosis and subsequent endothelial integrity disruption. These results demonstrated the critical role of prolonged and unresolved ER stress-induced IRE1α activation in modulating EC pyroptosis, leading to early endothelial cell injury and the acceleration of PAH progression.
如何引用
AMA
Xue-Yang Luo, Xue-Chun Li, Xiao Fu, Yu-Yang Tian, Xin-Yi Li, Zhen Zhang, et al. Endoplasmic Reticulum Stress-Induced Endothelial Cell Pyroptosis Contributes to Pulmonary Vascular Remodeling and Pulmonary Arterial Hypertension via IRE1α/Caspase-3/GSDME Pathway.. Journal of the American Heart Association. 2026; doi:10.1161/JAHA.125.043577.
APA
Xue-Yang Luo, Xue-Chun Li, Xiao Fu, Yu-Yang Tian, Xin-Yi Li, Zhen Zhang, et al (2026). Endoplasmic Reticulum Stress-Induced Endothelial Cell Pyroptosis Contributes to Pulmonary Vascular Remodeling and Pulmonary Arterial Hypertension via IRE1α/Caspase-3/GSDME Pathway.. Journal of the American Heart Association. https://doi.org/10.1161/JAHA.125.043577
GB/T 7714
Xue-Yang Luo, Xue-Chun Li, Xiao Fu, Yu-Yang Tian, Xin-Yi Li, Zhen Zhang, et al. Endoplasmic Reticulum Stress-Induced Endothelial Cell Pyroptosis Contributes to Pulmonary Vascular Remodeling and Pulmonary Arterial Hypertension via IRE1α/Caspase-3/GSDME Pathway.[J]. Journal of the American Heart Association, 2026 doi:10.1161/JAHA.125.043577.
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