Vorbe Julie, Massey Florence, Rocher Corinne, Morales Océane, Brikci Nihal, Le Borgne Marie, Giuseppina Caligiuri, Nicoletti Antonino, Franck Grégory, Illiano Stéphane
Université Paris Cité and Université Sorbonne Paris Nord, INSERM, LVTS, F-75018, Paris, France.
Cardiovascular Department Sanofi R&D, 1, avenue Pierre Brossolette, Chilly-Mazarin, France.
PLoS One. 2025 May 7;20(5):e0315119. doi: 10.1371/journal.pone.0315119. eCollection 2025.
Fever is an evolutionarily conserved and adaptive response during infections. However, prolonged fever has numerous systemic metabolic and functional side effects. In the heart, prolonged fever associated with infection is linked to fatal adverse effects, particularly involving impaired coronary circulation. Yet, the direct relationship between elevated temperature and coronary microcirculation dysfunction, remains to be fully demonstrated. In this study, we aimed to explore the specific responses of human coronary artery endothelial cells (HCAECs) to fever-range hyperthermia.
HCAECs were cultured at either 37°C or 40°C for up to 24 hours. Transcriptomic and proteomic profiles were obtained through microarray and mass spectrometry after 6, 12, and 24 hours of exposure. Key signaling pathways, upstream regulators, and candidate mechanisms were identified and validated at the mRNA and protein levels using mechanistic approaches.
Prolonged hyperthermia compromised HCAEC function, evidenced by cell detachment, loss of junctions, and increased permeability. HCAECs rapidly activated the unfolded protein response (UPR), including IRE1α activation and XBP1 splicing. Additionally, autophagic flux was significantly elevated, participating in the degradation of junction proteins. Pharmacological inhibition of IRE1α reduced the autophagic burden, protected against cell detachment, and preserved junction integrity over time.
Our findings reveal that in response to fever-range hyperthermia, the IRE1α-autophagy axis regulates the survival and function of coronary endothelial cells. This mechanism could play a key role in modulating endothelial responses during infection and contribute to the pathological outcomes of fever. Furthermore, it may be relevant in local inflammatory conditions with elevated temperatures.
发热是感染期间一种进化上保守的适应性反应。然而，长时间发热会产生许多全身性代谢和功能副作用。在心脏方面，与感染相关的长时间发热与致命的不良反应有关，尤其涉及冠状动脉循环受损。然而，体温升高与冠状动脉微循环功能障碍之间的直接关系仍有待充分证实。在本研究中，我们旨在探索人冠状动脉内皮细胞（HCAECs）对发热范围高温的具体反应。
将HCAECs分别在37°C或40°C培养长达24小时。在暴露6、12和24小时后，通过微阵列和质谱获得转录组和蛋白质组图谱。使用机制方法在mRNA和蛋白质水平鉴定并验证关键信号通路、上游调节因子和候选机制。
长时间高温损害了HCAEC功能，表现为细胞脱离、连接丧失和通透性增加。HCAECs迅速激活未折叠蛋白反应（UPR），包括IRE1α激活和XBP1剪接。此外，自噬通量显著升高，参与连接蛋白的降解。IRE1α的药理学抑制降低了自噬负担，防止细胞脱离，并随着时间的推移保持连接完整性。
我们的研究结果表明，响应发热范围高温时，IRE1α-自噬轴调节冠状动脉内皮细胞的存活和功能。这一机制可能在调节感染期间的内皮反应中起关键作用，并导致发热的病理结果。此外，它可能与体温升高的局部炎症状态有关。
