Lactate induces vascular permeability via disruption of VE-cadherin in endothelial cells during sepsis.
Lactate induces vascular permeability via disruption of VE-cadherin in endothelial cells during sepsis.
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DOI：
10.1126/sciadv.abm8965
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发表时间：
2022-04-29
期刊：
影响因子：
13.6
通讯作者：
Li, Chuanfu
中科院分区：
文献类型：
--
作者：
Yang, Kun;Fan, Min;Wang, Xiaohui;Xu, Jingjing;Wang, Yana;Gill, P. Spencer;Ha, Tuanzhu;Liu, Li;Hall, Jennifer, V;Williams, David L.;Li, Chuanfu
循环乳酸水平是脓毒症的重要生物标志物，与脓毒症相关死亡率呈正相关。我们研究了乳酸是否在脓毒症中引起内皮屏障功能障碍中发挥生物学作用。我们发现，乳酸导致血管通透性和炎症器官功能障碍的CLP脓毒症。从机制上讲，乳酸盐诱导ERK依赖性激活钙蛋白酶1/2，用于VE-钙粘蛋白的蛋白水解裂解，导致内皮细胞中VE-钙粘蛋白的内吞作用增强。此外，我们发现ERK 2与VE-钙粘蛋白相互作用并稳定静息内皮细胞中的VE-钙粘蛋白复合物。乳酸诱导的ERK 2磷酸化促进ERK 2与VE-钙粘蛋白的解离。在体内抑制乳酸产生或乳酸受体GPR 81的遗传耗竭减轻血管通透性和多器官损伤，并改善多微生物败血症的生存结果。我们的研究表明，糖酵解产生的乳酸和内皮细胞之间的代谢串扰在脓毒症的病理生理学中起着关键作用。乳酸导致败血症中的血管损伤。
Circulating lactate levels are a critical biomarker for sepsis and are positively correlated with sepsis-associated mortality. We investigated whether lactate plays a biological role in causing endothelial barrier dysfunction in sepsis. We showed that lactate causes vascular permeability and worsens organ dysfunction in CLP sepsis. Mechanistically, lactate induces ERK-dependent activation of calpain1/2 for VE-cadherin proteolytic cleavage, leading to the enhanced endocytosis of VE-cadherin in endothelial cells. In addition, we found that ERK2 interacts with VE-cadherin and stabilizes VE-cadherin complex in resting endothelial cells. Lactate-induced ERK2 phosphorylation promotes ERK2 disassociation from VE-cadherin. In vivo suppression of lactate production or genetic depletion of lactate receptor GPR81 mitigates vascular permeability and multiple organ injury and improves survival outcome in polymicrobial sepsis. Our study reveals that metabolic cross-talk between glycolysis-derived lactate and the endothelium plays a critical role in the pathophysiology of sepsis. Lactate contributes to vascular injury in sepsis.
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