Endothelial LAT1 (SLC7A5) Mediates S-Nitrosothiol Import and Modulates Respiratory Sequelae of Red Blood Cell Transfusion In Vivo.
Endothelial LAT1 (SLC7A5) Mediates S-Nitrosothiol Import and Modulates Respiratory Sequelae of Red Blood Cell Transfusion In Vivo.
复制标题
内皮 LAT1 (SLC7A5) 介导 S-亚硝基硫醇输入并调节体内红细胞输注的呼吸后遗症。
DOI：
10.1055/s-0044-1782182
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发表时间：
2024
影响因子：
6.7
通讯作者：
McMahon,TimJ
中科院分区：
文献类型：
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作者：
Zhu,Hongmei;Auten,RichardL;Whorton,AugustusRichard;Mason,StanleyNicholas;Bock,CherylB;Kucera,GaryT;Kelleher,ZacharyT;Vose,AaronT;McMahon,TimJ
背景红细胞(RBC)与内皮细胞(ECs)的粘附性增加可能导致疟疾、镰状细胞病和糖尿病的器官功能障碍。红细胞通常输出一氧化氮(NO)衍生的血管信号，促进血液流动。S-亚硝硫醇(SNO)是在红细胞中形成的硫醇加合物，其前体NO在血红蛋白中发生氧化结合的变构转变。RBC按需输出这些血管调节性SNO，从而调节局部血流，防止RBC-EC黏附，而大(L系统)中性氨基酸转运体1(LAT1；SLC7A5)似乎介导RBC输出SNO。方法为了确定LAT1介导的ECs SNO输入和LAT1介导的SNO输入在RBC SNO依赖的RBC隔离和体内血氧调节中的作用，我们设计了LAT1fl/fl；CDh5-Cre+小鼠，其中可能的SNO转运体LAT1可以被诱导地耗竭(击倒，KD)在ECs(“LAT1ECKD”)。与野生型(他莫昔芬处理的LAT1fl/fl；Cdh5-Cre+−)小鼠的ECs相比，LAT1ECKD小鼠(他莫昔芬诱导的LAT1fl/fl；Cdh5-Cre+)小鼠的ECs在体外导入SNO的能力较差。在体内，去除LAT1内皮细胞可增加RBC在肺内的滞留，降低RBC输注后的血液氧合。结论这是首次在遗传小鼠模型中显示LAT1对内皮细胞SNO转运的作用。我们首次提供了通过LAT1协调RBC SNO输出和EC SNO输入的直接证据。通过LAT1的SNO流量调节输血后RBC-EC在肺内的滞留，它的破坏损害了肺的血氧代谢。
BackgroundIncreased adhesivity of red blood cells (RBCs) to endothelial cells (ECs) may contribute to organ dysfunction in malaria, sickle cell disease, and diabetes. RBCs normally export nitric oxide (NO)-derived vascular signals, facilitating blood flow. S-nitrosothiols (SNOs) are thiol adducts formed in RBCs from precursor NO upon the oxygenation-linked allosteric transition in hemoglobin. RBCs export these vasoregulatory SNOs on demand, thereby regulating regional blood flow and preventing RBC–EC adhesion, and the large (system L) neutral amino acid transporter 1 (LAT1; SLC7A5) appears to mediate SNO export by RBCs.MethodsTo determine the role of LAT1-mediated SNO import by ECs generally and of LAT1-mediated SNO import by ECs in RBC SNO-dependent modulation of RBC sequestration and blood oxygenation in vivo, we engineered LAT1fl/fl; Cdh5-Cre+mice, in which the putative SNO transporter LAT1 can be inducibly depleted (knocked down, KD) specifically in ECs (“LAT1ECKD”).ResultsWe show that LAT1 in mouse lung ECs mediates cellular SNO uptake. ECs from LAT1ECKDmice (tamoxifen-induced LAT1fl/fl; Cdh5-Cre+) import SNOs poorly ex vivo compared with ECs from wild-type (tamoxifen-treated LAT1fl/fl; Cdh5-Cre−) mice. In vivo, endothelial depletion of LAT1 increased RBC sequestration in the lung and decreased blood oxygenation after RBC transfusion.ConclusionThis is the first study showing a role for SNO transport by LAT1 in ECs in a genetic mouse model. We provide the first direct evidence for the coordination of RBC SNO export with EC SNO import via LAT1. SNO flux via LAT1 modulates RBC–EC sequestration in lungs after transfusion, and its disruption impairs blood oxygenation by the lung.