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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Dosier, LBM; Premkumar, VJ; Zhu, H; Akosman, I; Wempe, MF; McMahon, TJ

Published Date

  • June 2017

Published In

Volume / Issue

  • 117 / 7

Start / End Page

  • 1402 - 1411

PubMed ID

  • 28382373

Pubmed Central ID

  • 28382373

Electronic International Standard Serial Number (EISSN)

  • 2567-689X

International Standard Serial Number (ISSN)

  • 0340-6245

Digital Object Identifier (DOI)

  • 10.1160/TH16-05-0373

Language

  • eng