Antagonists of the system L neutral amino acid transporter (LAT) promote endothelial adhesivity of human red blood cells.
Repository Usage Stats
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.
Amino Acids, Cyclic
Amino Acid Transport System L
Human Umbilical Vein Endothelial Cells
In Vitro Techniques
Published Version (Please cite this version)10.1160/TH16-05-0373
Publication InfoMcMahon, Timothy; Dosier, Laura; Premkumar, Vikram J; Zhu, Hongmei; Akosman, Izzet; & Wempe, Michael F (2017). Antagonists of the system L neutral amino acid transporter (LAT) promote endothelial adhesivity of human red blood cells. Thrombosis and haemostasis, 117(7). pp. 1402-1411. 10.1160/TH16-05-0373. Retrieved from https://hdl.handle.net/10161/19095.
This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
More InfoShow full item record
Assistant Professor of Pediatrics
My research focuses on abnormal breathing in sleep including central sleep apnea, obstructive sleep apnea, snoring, and abnormal sleep in children with complex medical conditions.In my practice, I focus on pediatric diseases of the lungs and sleep. I think that it is important to collaborate with primary care providers and families to create individualized care plans for each of my patients.
Professor of Medicine
The McMahon Lab at Duke University and Durham VA Medical Center is investigating novel roles of the red blood cell (RBC) in the circulation. The regulated release of the vasodilator SNO (a form of NO, nitric oxide) by RBCs within the respiratory cycle in mammals optimizes nutrient delivery at multiple levels, especially in the lung (gas exchange) and the peripheral microcirculation (O2 transport to tisses). Deficiency of RBC SNO bioactivity (as in human RBCs banked for transfusion), f
Alphabetical list of authors with Scholars@Duke profiles.