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

Publication ,  Journal Article
Dosier, LBM; Premkumar, VJ; Zhu, H; Akosman, I; Wempe, MF; McMahon, TJ
Published in: Thromb Haemost
June 28, 2017

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.

Duke Scholars

Published In

Thromb Haemost

DOI

EISSN

2567-689X

Publication Date

June 28, 2017

Volume

117

Issue

7

Start / End Page

1402 / 1411

Location

Germany

Related Subject Headings

  • Tyrosine
  • S-Nitrosothiols
  • Reticulocytes
  • RNA, Messenger
  • Mice, Nude
  • Mice
  • Leucine
  • In Vitro Techniques
  • Humans
  • Human Umbilical Vein Endothelial Cells
 

Citation

APA
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MLA
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Dosier, L. B. M., Premkumar, V. J., Zhu, H., Akosman, I., Wempe, M. F., & McMahon, T. J. (2017). Antagonists of the system L neutral amino acid transporter (LAT) promote endothelial adhesivity of human red blood cells. Thromb Haemost, 117(7), 1402–1411. https://doi.org/10.1160/TH16-05-0373
Dosier, Laura Beth Mann, Vikram J. Premkumar, Hongmei Zhu, Izzet Akosman, Michael F. Wempe, and Timothy J. McMahon. “Antagonists of the system L neutral amino acid transporter (LAT) promote endothelial adhesivity of human red blood cells.Thromb Haemost 117, no. 7 (June 28, 2017): 1402–11. https://doi.org/10.1160/TH16-05-0373.
Dosier LBM, Premkumar VJ, Zhu H, Akosman I, Wempe MF, McMahon TJ. Antagonists of the system L neutral amino acid transporter (LAT) promote endothelial adhesivity of human red blood cells. Thromb Haemost. 2017 Jun 28;117(7):1402–11.
Dosier, Laura Beth Mann, et al. “Antagonists of the system L neutral amino acid transporter (LAT) promote endothelial adhesivity of human red blood cells.Thromb Haemost, vol. 117, no. 7, June 2017, pp. 1402–11. Pubmed, doi:10.1160/TH16-05-0373.
Dosier LBM, Premkumar VJ, Zhu H, Akosman I, Wempe MF, McMahon TJ. Antagonists of the system L neutral amino acid transporter (LAT) promote endothelial adhesivity of human red blood cells. Thromb Haemost. 2017 Jun 28;117(7):1402–1411.
Journal cover image

Published In

Thromb Haemost

DOI

EISSN

2567-689X

Publication Date

June 28, 2017

Volume

117

Issue

7

Start / End Page

1402 / 1411

Location

Germany

Related Subject Headings

  • Tyrosine
  • S-Nitrosothiols
  • Reticulocytes
  • RNA, Messenger
  • Mice, Nude
  • Mice
  • Leucine
  • In Vitro Techniques
  • Humans
  • Human Umbilical Vein Endothelial Cells