Antagonists of the system L neutral amino acid transporter (LAT) promote endothelial adhesivity of human red blood cells.
Antagonists of the system L neutral amino acid transporter (LAT) promote endothelial adhesivity of human red blood cells.
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L 中性氨基酸转运蛋白 (LAT) 系统的拮抗剂可促进人红细胞的内皮粘附性。
DOI：
10.1160/th16-05-0373
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发表时间：
2017
影响因子：
6.7
通讯作者：
McMahon,TimothyJ
中科院分区：
文献类型：
--
作者：
Dosier,LauraBethMann;Premkumar,VikramJ;Zhu,Hongmei;Akosman,Izzet;Wempe,MichaelF;McMahon,TimothyJ
L 系统中性氨基酸转运蛋白（LAT；LAT1、LAT2、LAT3 或 LAT4）在人类生物学中具有多种功能，包括细胞输入 S-亚硝基硫醇 (SNO)、一氧化氮 (NO) 的生物活性衍生物。红细胞 (RBC) 内血红蛋白形成的 SNO 已被研究，但 SNO 离开红细胞的通道仍不清楚。在这里，我们假设 RBC 输出的 SNO 也可能依赖于 LAT 活性，并研究了 RBC LAT 在调节 SNO 敏感的 RBC-内皮细胞 (EC) 粘附中的作用。我们在体外和体内使用多种 LAT 药理学抑制剂来测试 LAT 在 RBC 输出 SNO 中的作用，从而调节 RBC-EC 粘附。 1型特异性或非特异性LAT拮抗剂对人红细胞LAT的抑制增加了体外红细胞内皮粘附性，而LAT抑制剂往往会增加输血后红细胞在肺中的隔离并减少体内氧合。 LAT1 特异性抑制剂减弱了红细胞的 SNO 输出，我们证明了红细胞膜中的 LAT1 和网织红细胞中的 LAT1 mRNA。抑制 LAT1 的促粘附作用可以通过补充 L-CSNO（S-亚硝基-L-半胱氨酸）来克服，但不能通过 D-CSNO 或 L-Cys 来克服，这表明立体特异性细胞间 SNO 转运具有基础抗粘附作用。这项研究首次揭示了 LAT1 在从红细胞中输出 SNO 以防止其粘附到 EC 中的新作用。这些发现对细胞间 SNO 信号传导机制、血栓形成、镰状细胞病和红细胞储存后输注（当红细胞粘附性增加时）具有重要意义。
The system L neutral amino acid transporter (LAT; LAT1, LAT2, LAT3, or LAT4) has multiple functions in human biology, including the cellular import of S-nitrosothiols (SNOs), biologically active derivatives of nitric oxide (NO). SNO formation by haemoglobin within red blood cells (RBC) has been studied, but the conduit whereby a SNO leaves the RBC remains unidentified. Here we hypothesised that SNO export by RBCs may also depend on LAT activity, and investigated the role of RBC LAT in modulating SNO-sensitive RBC-endothelial cell (EC) adhesion. We used multiple pharmacologic inhibitors of LATin vitroandin vivoto test the role of LAT in SNO export from RBCs and in thereby modulating RBC-EC adhesion. Inhibition of human RBC LAT by type-1-specific or nonspecific LAT antagonists increased RBC-endothelial adhesivityin vitro, and LAT inhibitors tended to increase post-transfusion RBC sequestration in the lung and decreased oxygenationin vivo. A LAT1-specific inhibitor attenuated SNO export from RBCs, and we demonstrated LAT1 in RBC membranes and LAT1 mRNA in reticulocytes. The proadhesive effects of inhibiting LAT1 could be overcome by supplemental L-CSNO (S-nitroso-L-cysteine), but not D-CSNO or L-Cys, and suggest a basal anti-adhesive role for stereospecific intercellular SNO transport. This study reveals for the first time a novel role of LAT1 in the export of SNOs from RBCs to prevent their adhesion to ECs. The findings have implications for the mechanisms of intercellular SNO signalling, and for thrombosis, sickle cell disease, and post-storage RBC transfusion, when RBC adhesivity is increased.