Endothelial LAT1 (SLC7A5) Mediates S-Nitrosothiol Import and Modulates Respiratory Sequelae of Red Blood Cell Transfusion In Vivo

Increased 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 RB...

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Bibliographic Details
Published in:	Thrombosis and haemostasis Vol. 124; no. 7; p. 656
Main Authors:	Zhu, Hongmei, Auten, Richard L, Whorton, Augustus Richard, Mason, Stanley Nicholas, Bock, Cheryl B, Kucera, Gary T, Kelleher, Zachary T, Vose, Aaron T, McMahon, Tim J
Format:	Journal Article
Language:	English
Published:	Germany 01-07-2024
Subjects:	Animals Cell Adhesion Endothelial Cells - metabolism Erythrocyte Transfusion Erythrocytes - metabolism Humans Large Neutral Amino Acid-Transporter 1 - genetics Large Neutral Amino Acid-Transporter 1 - metabolism Lung - metabolism Mice Mice, Inbred C57BL Nitric Oxide - metabolism S-Nitrosothiols - metabolism
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Summary:	Increased 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. To 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 LAT1 ; Cdh5-Cre mice, in which the putative SNO transporter LAT1 can be inducibly depleted (knocked down, KD) specifically in ECs ("LAT1 "). We show that LAT1 in mouse lung ECs mediates cellular SNO uptake. ECs from LAT1 mice (tamoxifen-induced LAT1 ; Cdh5-Cre ) import SNOs poorly ex vivo compared with ECs from wild-type (tamoxifen-treated LAT1 ; Cdh5-Cre ) mice. In vivo, endothelial depletion of LAT1 increased RBC sequestration in the lung and decreased blood oxygenation after RBC transfusion. This 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.
ISSN:	2567-689X
DOI:	10.1055/s-0044-1782182