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

dc.contributor.author

Zhu, Hongmei

dc.contributor.author

Auten, Richard L

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Whorton, Augustus Richard

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Mason, Stanley Nicholas

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Bock, Cheryl B

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Kucera, Gary T

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Kelleher, Zachary T

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Vose, Aaron T

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McMahon, Tim J

dc.date.accessioned

2024-04-01T20:03:50Z

dc.date.available

2024-04-01T20:03:50Z

dc.date.issued

2024-03

dc.description.abstract

Background

 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.

Methods

 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 LAT1fl/fl; Cdh5-Cre+ mice, in which the putative SNO transporter LAT1 can be inducibly depleted (knocked down, KD) specifically in ECs ("LAT1ECKD").

Results

 We show that LAT1 in mouse lung ECs mediates cellular SNO uptake. ECs from LAT1ECKD mice (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.

Conclusion

 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.
dc.identifier.issn

0340-6245

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2567-689X

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https://hdl.handle.net/10161/30457

dc.language

eng

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Thrombosis and haemostasis

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10.1055/s-0044-1782182

dc.rights.uri

https://creativecommons.org/licenses/by-nc/4.0

dc.title

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

dc.type

Journal article

duke.contributor.orcid

McMahon, Tim J|0000-0002-3404-3223

pubs.organisational-group

Duke

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School of Medicine

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Clinical Science Departments

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Medicine

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Medicine, Pulmonary, Allergy, and Critical Care Medicine

pubs.publication-status

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