乳酸盐通过AMPK-mTOR-TFEB-CX43轴促进自噬,有助于远程缺血预处理介导的心肌缺血再灌注损伤保护。

IF 4.7 2区 医学 Q1 PATHOLOGY American Journal of Pathology Pub Date : 2024-07-26 DOI:10.1016/j.ajpath.2024.07.005
Zhang-Jian Yang , Wei-Fang Zhang , Qing-Qing Jin , Zhi-Rong Wu , Yun-Yan Du , Hao Shi , Zhen-Sheng Qu , Xiao-Jian Han , Li-Ping Jiang
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Furthermore, AZD3965, a selective monocarboxylate transporter 1 inhibitor, and 2-deoxy-<span>d</span>-glucose, a glycolysis inhibitor, mitigated the effects of RIPC-induced elevated lactate in the myocardium and prevented RIPC against myocardial I/R injury. In an <em>in vitro</em> hypoxia/reoxygenation model, lactate markedly mitigated hypoxia/reoxygenation-induced cell damage in H9c2 cells. Further studies suggested that lactate contributed to RIPC, rescuing I/R-induced autophagy deficiency by promoting transcription factor EB (TFEB) translocation to the nucleus through activating the AMP-activated protein kinase (AMPK)–mammalian target of rapamycin (mTOR) pathway without influencing the phosphatidylinositol 3-kinase–Akt pathway, thus reducing cardiomyocyte damage. Interestingly, lactate up-regulated the mRNA and protein expression of connexin 43 (CX43) by facilitating the binding of TFEB to CX43 promoter in the myocardium. 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引用次数: 0

摘要

远程缺血预处理(RIPC)通过释放各种体液因子对心肌缺血再灌注(I/R)损伤起到保护作用。乳酸是缺血组织中常见的代谢产物。然而,人们对乳酸在心肌缺血再灌注损伤中的作用及其内在机制知之甚少。本研究发现,RIPC 会升高血液和心肌中的乳酸水平。此外,选择性单羧酸盐转运体 1(MCT1)抑制剂 AZD3965 和糖酵解抑制剂 2-脱氧-D-葡萄糖(2-DG)可减轻 RIPC 引起的心肌乳酸升高的影响,并防止 RIPC 对心肌 I/R 损伤的影响。在体外缺氧再氧合(H/R)模型中,乳酸盐明显减轻了 H9c2 细胞因 H/R 引起的细胞损伤。同时,进一步的研究表明,乳酸盐通过激活 AMPK-mTOR 通路促进 TFEB 转位至细胞核,而不影响 PI3K-Akt 通路,有助于 RIPC 挽救 I/R 诱导的自噬缺陷,从而减轻心肌细胞损伤。有趣的是,我们还发现乳酸通过促进 TFEB 与心肌中 CX43 启动子的结合,上调了 CX43 的 mRNA 和蛋白表达。从功能上讲,沉默 TFEB 可减弱乳酸盐对细胞损伤的保护作用,而过量表达 CX43 则可逆转这种作用。进一步的机理研究表明,乳酸通过AMPK-mTOR-TFEB信号通路促进了CX43调控的自噬。总之,我们的研究表明,RIPC 可通过 AMPK-mTOR-TFEB-CX43 轴乳酸介导的心肌自噬保护心肌 I/R 损伤。
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Lactate Contributes to Remote Ischemic Preconditioning–Mediated Protection Against Myocardial Ischemia Reperfusion Injury by Facilitating Autophagy via the AMP-Activated Protein Kinase–Mammalian Target of Rapamycin–Transcription Factor EB–Connexin 43 Axis
Remote ischemic preconditioning (RIPC) exerts a protective role on myocardial ischemia/reperfusion (I/R) injury by the release of various humoral factors. Lactate is a common metabolite in ischemic tissues. Nevertheless, little is known about the role lactate plays in myocardial I/R injury and its underlying mechanism. This investigation revealed that RIPC elevated the level of lactate in blood and myocardium. Furthermore, AZD3965, a selective monocarboxylate transporter 1 inhibitor, and 2-deoxy-d-glucose, a glycolysis inhibitor, mitigated the effects of RIPC-induced elevated lactate in the myocardium and prevented RIPC against myocardial I/R injury. In an in vitro hypoxia/reoxygenation model, lactate markedly mitigated hypoxia/reoxygenation-induced cell damage in H9c2 cells. Further studies suggested that lactate contributed to RIPC, rescuing I/R-induced autophagy deficiency by promoting transcription factor EB (TFEB) translocation to the nucleus through activating the AMP-activated protein kinase (AMPK)–mammalian target of rapamycin (mTOR) pathway without influencing the phosphatidylinositol 3-kinase–Akt pathway, thus reducing cardiomyocyte damage. Interestingly, lactate up-regulated the mRNA and protein expression of connexin 43 (CX43) by facilitating the binding of TFEB to CX43 promoter in the myocardium. Functionally, silencing of TFEB attenuated the protective effect of lactate on cell damage, which was reversed by overexpression of CX43. Further mechanistic studies suggested that lactate facilitated CX43-regulated autophagy via the AMPK-mTOR-TFEB signaling pathway. Collectively, this research demonstrates that RIPC protects against myocardial I/R injury through lactate-mediated myocardial autophagy via the AMPK-mTOR-TFEB-CX43 axis.
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来源期刊
CiteScore
11.40
自引率
0.00%
发文量
178
审稿时长
30 days
期刊介绍: The American Journal of Pathology, official journal of the American Society for Investigative Pathology, published by Elsevier, Inc., seeks high-quality original research reports, reviews, and commentaries related to the molecular and cellular basis of disease. The editors will consider basic, translational, and clinical investigations that directly address mechanisms of pathogenesis or provide a foundation for future mechanistic inquiries. Examples of such foundational investigations include data mining, identification of biomarkers, molecular pathology, and discovery research. Foundational studies that incorporate deep learning and artificial intelligence are also welcome. High priority is given to studies of human disease and relevant experimental models using molecular, cellular, and organismal approaches.
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