LACTATE IMPAIRS VASCULAR PERMEABILITY BY INHIBITING HSPA12B EXPRESSION VIA GPR81-DEPENDENT SIGNALING IN SEPSIS.
LACTATE IMPAIRS VASCULAR PERMEABILITY BY INHIBITING HSPA12B EXPRESSION VIA GPR81-DEPENDENT SIGNALING IN SEPSIS.
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DOI：
10.1097/shk.0000000000001983
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发表时间：
2022-10-01
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影响因子：
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简介：败血症损害血管完整性导致多器官衰竭。循环乳酸水平与脓毒症引起的死亡率呈正相关。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起作用。方法：采用盲肠结扎穿孔法（CLP）建立小鼠多菌性脓毒症模型。在CLP或假手术后6 h腹腔注射乳酸（pH 6.8，0.5 g/kg体重）。为了阐明热休克蛋白A12 B（HSPA 12 B）的作用，对野生型、HSPA 12 B转基因和内皮HSPA 12 B缺陷小鼠进行CLP或假手术。为了抑制乳酸信号传导，在手术前3 h腹膜内注射3 OBA（120 μM）。采用伊文思蓝染料渗透试验评价血管通透性。结果：我们发现，乳酸的管理提高CLP诱导的血管通透性。血管内皮钙粘蛋白（VE-钙粘蛋白），claudin 5和封闭小带1（ZO-1）在维持内皮细胞连接和血管完整性中起着至关重要的作用。乳酸盐给药显着降低了脓毒症小鼠心脏中VE-钙粘蛋白、密蛋白5和ZO-1的表达。我们的体外数据显示，乳酸盐（10 mM）处理破坏了内皮细胞中的VE-钙粘蛋白、紧密连接蛋白5和ZO-1。从机制上讲，我们观察到乳酸通过减少HSPA 12 B的表达促进VE-钙粘蛋白的内吞作用。HSPA 12 B的过表达防止乳酸诱导的VE-钙粘蛋白紊乱。G蛋白偶联受体81（GPR 81）是乳酸的特异性受体。用GPR 81拮抗剂3 OBA抑制GPR 81可降低脓毒症小鼠血管通透性并逆转HSPA 12 B表达。结论：目前的研究表明，乳酸通过减少内皮细胞中VE-钙粘蛋白连接和紧密连接来促进血管通透性。乳酸在血管通透性过高中的有害作用是通过HSPA 12 B和GPR 81依赖性信号传导介导的。
Introduction: Sepsis impaired vascular integrity results in multiple organ failure. Circulating lactate level is positively correlated with sepsis-induced mortality. We investigated whether lactate plays a role in causing endothelial barrier dysfunction in sepsis. Methods: Polymicrobial sepsis was induced in mice by cecal ligation and puncture (CLP). Lactic acid was injected i.p. (pH 6.8, 0.5 g/kg body weight) 6 h after CLP or sham surgery. To elucidate the role of heat shock protein A12B (HSPA12B), wild-type, HSPA12B-transgenic, and endothelial HSPA12B-deficient mice were subjected to CLP or sham surgery. To suppress lactate signaling, 3OBA (120 μM) was injected i.p. 3 h before surgery. Vascular permeability was evaluated with the Evans blue dye penetration assay. Results: We found that administration of lactate elevated CLP-induced vascular permeability. Vascular endothelial cadherin (VE-cadherin), claudin 5, and zonula occluden 1 (ZO-1) play a crucial role in the maintenance of endothelial cell junction and vascular integrity. Lactate administration significantly decreased VE-cadherin, claudin 5, and ZO-1 expression in the heart of septic mice. Our in vitro data showed that lactate (10 mM) treatment disrupted VE-cadherin, claudin 5, and ZO-1 in endothelial cells. Mechanistically, we observed that lactate promoted VE-cadherin endocytosis by reducing the expression of HSPA12B. Overexpression of HSPA12B prevented lactate-induced VE-cadherin disorganization. G protein–coupled receptor 81 (GPR81) is a specific receptor for lactate. Inhibition of GPR81 with its antagonist 3OBA attenuated vascular permeability and reversed HSPA12B expression in septic mice. Conclusions: The present study demonstrated a novel role of lactate in promoting vascular permeability by decreasing VE-cadherin junctions and tight junctions in endothelial cells. The deleterious effects of lactate in vascular hyperpermeability are mediated via HSPA12B- and GPR81-dependent signaling.
血浆 HSPA12B 是严重败血症预后不良的潜在预测因子
影响因子：
3.7
作者：
Zhang R;Wan XJ;Zhang X;Kang QX;Bian JJ;Yu GF;Wang JF;Zhu KM
通讯作者：
Zhu KM