Hypothermic oxygenated perfusion attenuates DCD liver ischemia-reperfusion injury by activating the JAK2/STAT3/HAX1 pathway to regulate endoplasmic reticulum stress.
Hypothermic oxygenated perfusion attenuates DCD liver ischemia-reperfusion injury by activating the JAK2/STAT3/HAX1 pathway to regulate endoplasmic reticulum stress.
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低温含氧灌注通过激活JAK2/STAT3/HAX1途径来调节内质网应激，从而减弱DCD肝缺血再灌注损伤。
DOI：
10.1186/s11658-023-00466-5
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发表时间：
2023-07-12
影响因子：
8.3
通讯作者：
中科院分区：
文献类型：
--
作者：
心脏死亡(DCD)供者供体的肝脏缺血再灌注损伤(IRI)是决定移植成功的主要因素。内质网应激在肝脏IRI中起关键作用，可能涉及Janus kinase2/信号转导和转录激活因子3(JAK2/STAT3)通路和抗凋亡蛋白造血祖细胞底物-1相关蛋白X-1(HAX1)。本研究旨在探讨低温氧合灌流(HOPE)对DCD大鼠肝脏IRI时内质网应激和细胞凋亡的影响。为了探讨HOPE是否能改善DCD肝脏的IRI，采用Western blotting和实时定量聚合酶链式反应检测不同相关蛋白的水平。通过进一步的表达分析、免疫组织化学分析、免疫荧光染色、末端脱氧核苷酸转移酶介导的dUTP缺口末端标记(TUNEL)染色和透射电子显微镜分析HOPE对内质网应激和细胞凋亡的影响。为了阐明JAK2/STAT3通路和HAX1在这一过程中的作用，我们进行了AG490抑制剂、JAX1质粒转染、免疫共沉淀(CO-IP)和流式细胞术分析。HOPE可减轻DCD模型大鼠的肝脏损伤和炎症反应，同时减轻ER应激和细胞凋亡。在机制上，HOPE通过激活JAK2/STAT3途径抑制未折叠蛋白的反应，从而减少内质网应激和细胞凋亡。此外，激活的JAK2/STAT3通路上调了HAX1，促进了HAX1与SERCA2b之间的相互作用，以维持内质网钙稳态。上调的HAX1还通过抑制肌醇需求酶1(IRE1)途径来调节内质网应激和细胞凋亡。JAK2/STAT3介导的HAX1在HOPE过程中上调可减轻肝脏ER应激和细胞凋亡，提示JAK2/STAT3/HAX1通路是DCD肝移植中IRI处理的潜在靶点。网上版载有补充材料，可在10.1186/s11658.023-00466-5查阅。
Hepatic ischemia–reperfusion injury (IRI) in donation after cardiac death (DCD) donors is a major determinant of transplantation success. Endoplasmic reticulum (ER) stress plays a key role in hepatic IRI, with potential involvement of the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway and the antiapoptotic protein hematopoietic-lineage substrate-1-associated protein X-1 (HAX1). In this study, we aimed to investigate the effects of hypothermic oxygenated perfusion (HOPE), an organ preservation modality, on ER stress and apoptosis during hepatic IRI in a DCD rat model. To investigate whether HOPE could improve IRI in DCD livers, levels of different related proteins were examined by western blotting and quantitative real-time polymerase chain reaction. Further expression analyses, immunohistochemical analyses, immunofluorescence staining, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining, and transmission electron microscopy were conducted to analyze the effects of HOPE on ER stress and apoptosis. To clarify the role of the JAK2/STAT3 pathway and HAX1 in this process, AG490 inhibitor, JAX1 plasmid transfection, co-immunoprecipitation (CO-IP), and flow cytometry analyses were conducted. HOPE reduced liver injury and inflammation while alleviating ER stress and apoptosis in the DCD rat model. Mechanistically, HOPE inhibited unfolded protein responses by activating the JAK2/STAT3 pathway, thus reducing ER stress and apoptosis. Moreover, the activated JAK2/STAT3 pathway upregulated HAX1, promoting the interaction between HAX1 and SERCA2b to maintain ER calcium homeostasis. Upregulated HAX1 also modulated ER stress and apoptosis by inhibiting the inositol-requiring enzyme 1 (IRE1) pathway. JAK2/STAT3-mediated upregulation of HAX1 during HOPE alleviates hepatic ER stress and apoptosis, indicating the JAK2/STAT3/HAX1 pathway as a potential target for IRI management during DCD liver transplantation. The online version contains supplementary material available at 10.1186/s11658-023-00466-5.
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影响因子：
5.6
作者：
Folch-Puy E;Panisello A;Oliva J;Lopez A;Castro Benítez C;Adam R;Roselló-Catafau J
通讯作者：
Roselló-Catafau J
影响因子：
25.7
作者：
Dutkowski, Philipp;Schlegel, Andrea;Clavien, Pierre-Alain
通讯作者：
Clavien, Pierre-Alain
牛磺熊去氧胆酸和4-苯基丁酸减轻大鼠心死亡肝移植后内质网应激并改善捐献预后
DOI：
10.1016/s1499-3872(14)60269-1
发表时间：
2014-12-15
影响因子：
3.3
作者：
Lu, Hao;Lu, Ling;Zhang, Feng
通讯作者：
Zhang, Feng
DOI：
10.15252/embj.2021108690
发表时间：
2022-12-17
期刊：
The EMBO journal
影响因子：
--
作者：
Flores-Romero H;Hohorst L;John M;Albert MC;King LE;Beckmann L;Szabo T;Hertlein V;Luo X;Villunger A;Frenzel LP;Kashkar H;Garcia-Saez AJ
通讯作者：
Garcia-Saez AJ
影响因子：
15.9
作者：
Fan, Yanxin;Murgia, Marta;Linder, Monika, I;Mizoguchi, Yoko;Wang, Cong;Lyszkiewicz, Marcin;Zietara, Natalia;Liu, Yanshan;Frenz, Stephanie;Sciuccati, Gabriela;Partida-Gaytan, Armando;Alizadeh, Zahra;Rezaei, Nima;Rehling, Peter;Dennerlein, Sven;Mann, Matthias;Klein, Christoph
通讯作者：
Klein, Christoph