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PLoS One. 2014 Jan 15;9(1):e85730. doi: 10.1371/journal.pone.0085730. eCollection 2014.

Sodium-coupled neutral amino acid transporter 1 (SNAT1) modulates L-citrulline transport and nitric oxide (NO) signaling in piglet pulmonary arterial endothelial cells.

Author information

1
Dept. of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America ; Monroe Carell Jr. Children's Hospital at Vanderbilt, Nashville, Tennessee, United States of America.
2
Dept of Pediatrics, Albert Einstein College of Medicine and the Children's Hospital at Montefiore, New York, New York, United States of America.
3
Dept. of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America ; Monroe Carell Jr. Children's Hospital at Vanderbilt, Nashville, Tennessee, United States of America ; Vanderbilt Center for Molecular Toxicology, Nashville, Tennessee, United States of America.
4
Division of Genetics and Metabolism, Children's National Medical Center, Washington, District of Columbia, United States of America.

Abstract

RATIONALE:

There is evidence that impairments in nitric oxide (NO) signaling contribute to chronic hypoxia-induced pulmonary hypertension. The L-arginine-NO precursor, L-citrulline, has been shown to ameliorate pulmonary hypertension. Sodium-coupled neutral amino acid transporters (SNATs) are involved in the transport of L-citrulline into pulmonary arterial endothelial cells (PAECs). The functional link between the SNATs, L-citrulline, and NO signaling has not yet been explored.

OBJECTIVE:

We tested the hypothesis that changes in SNAT1 expression and transport function regulate NO production by modulating eNOS coupling in newborn piglet PAECs.

METHODS AND RESULTS:

A silencing RNA (siRNA) technique was used to assess the contribution of SNAT1 to NO production and eNOS coupling (eNOS dimer-to-monomer ratios) in PAECs from newborn piglets cultured under normoxic and hypoxic conditions in the presence and absence of L-citrulline. SNAT1 siRNA reduced basal NO production in normoxic PAECs and prevented L-citrulline-induced elevations in NO production in both normoxic and hypoxic PAECs. SNAT1 siRNA reduced basal eNOS dimer-to-monomer ratios in normoxic PAECs and prevented L-citrulline-induced increases in eNOS dimer-to-monomer ratios in hypoxic PAECs.

CONCLUSIONS:

SNAT1 mediated L-citrulline transport modulates eNOS coupling and thus regulates NO production in hypoxic PAECs from newborn piglets. Strategies that increase SNAT1-mediated transport and supply of L-citrulline may serve as novel therapeutic approaches to enhance NO production in patients with pulmonary vascular disease.

PMID:
24454923
PMCID:
PMC3893279
DOI:
10.1371/journal.pone.0085730
[Indexed for MEDLINE]
Free PMC Article
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