Prolonged hypoxia augments L-citrulline transport by System A in the newborn piglet pulmonary circulation

Candice D. Fike, Marta Sidoryk-Wegrzynowicz, Michael Aschner, Marshall Summar, Lawrence S. Prince, Gary Cunningham, Mark Kaplowitz, Yongmei Zhang, Judy L. Aschner

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

Aims: Pulmonary arterial endothelial cells (PAECs) express the enzymes needed for generation of L-arginine from intracellular L-citrulline but do not express the enzymes needed for de novo L-citrulline synthesis. Hence, L-citrulline levels in PAECs are dependent on L-citrulline transport. Once generated, L-arginine can be converted to L-citrulline and nitric oxide (NO) by the enzyme NO synthase. We sought to determine whether hypoxia, a condition aetiologically linked to pulmonary hypertension, alters the transport of L-citrulline and the expression of the sodium-coupled neutral amino acid transporters (SNATs) in PAECs from newborn piglets. Methods and results: PAECs isolated from newborn piglets were cultured under normoxic and hypoxic conditions and used to measure SNAT1, 2, 3, and 5 protein expression and 14C-L-citrulline uptake. SNAT1 protein expression was increased, while SNAT2, SNAT3, and SNAT5 expression was unaltered in hypoxic PAECs. 14C-L-citrulline uptake was increased in hypoxic PAECs. Studies with inhibitors of System A (SNAT1/2) and System N (SNAT3/5) revealed that the increased 14C-L-citrulline uptake was largely due to System A-mediated transport. Additional studies were performed to evaluate SNAT protein expression and L-citrulline levels in lungs of piglets with chronic hypoxia-induced pulmonary hypertension and comparable age controls. Lungs from piglets raised in chronic hypoxia exhibited greater SNAT1 expression and higher L-citrulline levels than lungs from controls. Conclusion: Increased SNAT1 expression and the concomitant enhanced ability to transport L-citrulline in PAECs could represent an important regulatory mechanism to counteract NO signalling impairments known to occur during the development of chronic hypoxia-induced pulmonary hypertension in newborns.

Original languageEnglish (US)
Pages (from-to)375-384
Number of pages10
JournalCardiovascular research
Volume95
Issue number3
DOIs
StatePublished - Dec 1 2012

    Fingerprint

Keywords

  • Nitric oxide
  • Pulmonary hypertension
  • Sodium-coupled neutral amino acid transporters

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Fike, C. D., Sidoryk-Wegrzynowicz, M., Aschner, M., Summar, M., Prince, L. S., Cunningham, G., Kaplowitz, M., Zhang, Y., & Aschner, J. L. (2012). Prolonged hypoxia augments L-citrulline transport by System A in the newborn piglet pulmonary circulation. Cardiovascular research, 95(3), 375-384. https://doi.org/10.1093/cvr/cvs186