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

Publication ,  Journal Article
Zhu, H; Auten, RL; Whorton, AR; Mason, SN; Bock, CB; Kucera, GT; Kelleher, ZT; Vose, AT; McMahon, TJ
Published in: Thromb Haemost
March 22, 2024

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.

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Published In

Thromb Haemost

DOI

EISSN

2567-689X

Publication Date

March 22, 2024

Location

Germany

Related Subject Headings

  • Cardiovascular System & Hematology
  • 3202 Clinical sciences
  • 3201 Cardiovascular medicine and haematology
  • 1103 Clinical Sciences
  • 1102 Cardiorespiratory Medicine and Haematology
 

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Zhu, H., Auten, R. L., Whorton, A. R., Mason, S. N., Bock, C. B., Kucera, G. T., … McMahon, T. J. (2024). Endothelial LAT1 (SLC7A5) Mediates S-Nitrosothiol Import and Modulates Respiratory Sequelae of Red Blood Cell Transfusion In Vivo. Thromb Haemost. https://doi.org/10.1055/s-0044-1782182
Zhu, Hongmei, Richard L. Auten, Augustus Richard Whorton, Stanley Nicholas Mason, Cheryl B. Bock, Gary T. Kucera, Zachary T. Kelleher, Aaron T. Vose, and Tim J. McMahon. “Endothelial LAT1 (SLC7A5) Mediates S-Nitrosothiol Import and Modulates Respiratory Sequelae of Red Blood Cell Transfusion In Vivo.Thromb Haemost, March 22, 2024. https://doi.org/10.1055/s-0044-1782182.
Zhu H, Auten RL, Whorton AR, Mason SN, Bock CB, Kucera GT, et al. Endothelial LAT1 (SLC7A5) Mediates S-Nitrosothiol Import and Modulates Respiratory Sequelae of Red Blood Cell Transfusion In Vivo. Thromb Haemost. 2024 Mar 22;
Zhu, Hongmei, et al. “Endothelial LAT1 (SLC7A5) Mediates S-Nitrosothiol Import and Modulates Respiratory Sequelae of Red Blood Cell Transfusion In Vivo.Thromb Haemost, Mar. 2024. Pubmed, doi:10.1055/s-0044-1782182.
Zhu H, Auten RL, Whorton AR, Mason SN, Bock CB, Kucera GT, Kelleher ZT, Vose AT, McMahon TJ. Endothelial LAT1 (SLC7A5) Mediates S-Nitrosothiol Import and Modulates Respiratory Sequelae of Red Blood Cell Transfusion In Vivo. Thromb Haemost. 2024 Mar 22;
Journal cover image

Published In

Thromb Haemost

DOI

EISSN

2567-689X

Publication Date

March 22, 2024

Location

Germany

Related Subject Headings

  • Cardiovascular System & Hematology
  • 3202 Clinical sciences
  • 3201 Cardiovascular medicine and haematology
  • 1103 Clinical Sciences
  • 1102 Cardiorespiratory Medicine and Haematology