Endoplasmic Reticulum Stress‐Induced Endothelial Cell Pyroptosis Contributes to Pulmonary Vascular Remodeling and Pulmonary Arterial Hypertension via IRE1α/Caspase‐3/GSDME Pathway

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.