Antagonists of the system L neutral amino acid transporter (LAT) promote endothelial adhesivity of human red blood cells.

dc.contributor.author

Dosier, Laura Beth Mann

dc.contributor.author

Premkumar, Vikram J

dc.contributor.author

Zhu, Hongmei

dc.contributor.author

Akosman, Izzet

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Wempe, Michael F

dc.contributor.author

McMahon, Timothy J

dc.date.accessioned

2019-07-12T19:28:10Z

dc.date.available

2019-07-12T19:28:10Z

dc.date.issued

2017-06

dc.date.updated

2019-07-12T19:28:09Z

dc.description.abstract

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 LAT in vitro and in vivo to 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 adhesivity in vitro, and LAT inhibitors tended to increase post-transfusion RBC sequestration in the lung and decreased oxygenation in 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.

dc.identifier

16-05-0373

dc.identifier.issn

0340-6245

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2567-689X

dc.identifier.uri

https://hdl.handle.net/10161/19095

dc.language

eng

dc.publisher

Georg Thieme Verlag KG

dc.relation.ispartof

Thrombosis and haemostasis

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10.1160/TH16-05-0373

dc.subject

Erythrocytes

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Reticulocytes

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Endothelial Cells

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Animals

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Humans

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Mice

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Mice, Nude

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S-Nitrosothiols

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Cysteine

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Benzoxazoles

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Leucine

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Amino Acids, Cyclic

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Tyrosine

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Amino Acid Transport System L

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RNA, Messenger

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Cell Adhesion

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Erythrocyte Deformability

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Human Umbilical Vein Endothelial Cells

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In Vitro Techniques

dc.title

Antagonists of the system L neutral amino acid transporter (LAT) promote endothelial adhesivity of human red blood cells.

dc.type

Journal article

duke.contributor.orcid

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

pubs.begin-page

1402

pubs.end-page

1411

pubs.issue

7

pubs.organisational-group

School of Medicine

pubs.organisational-group

Duke

pubs.organisational-group

Medicine, Pulmonary, Allergy, and Critical Care Medicine

pubs.organisational-group

Medicine

pubs.organisational-group

Clinical Science Departments

pubs.organisational-group

Pediatrics, Pulmonary and Sleep Medicine

pubs.organisational-group

Pediatrics

pubs.publication-status

Published

pubs.volume

117

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