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

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 (14)C-l-citrulline uptake. SNAT1 protein expression was increased, while SNAT2, SNAT3, and SNAT5 expression was unaltered in hypoxic PAECs. (14)C-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 (14)C-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.

• Authors: Candice D Fike, Marta Sidoryk-Wegrzynowicz, Michael Aschner, Marshall Summar, Lawrence S Prince, Gary Cunningham, Mark Kaplowitz, Yongmei Zhang, Judy L Aschner
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 95 Issue 3 Pg. 375-84 (Aug 01 2012) ISSN: 1755-3245 [Electronic] England
• PMID: 22673370 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Amino Acid Transport System A
• Membrane Transport Modulators
• Citrulline
• Nitric Oxide

Topics

• Amino Acid Transport System A (antagonists & inhibitors, metabolism)
• Animals
• Animals, Newborn
• Biological Transport
• Cells, Cultured
• Chronic Disease
• Citrulline (metabolism)
• Disease Models, Animal
• Endothelial Cells (drug effects, metabolism)
• Familial Primary Pulmonary Hypertension
• Hypertension, Pulmonary (etiology, metabolism, physiopathology)
• Hypoxia (complications, metabolism, physiopathology)
• Membrane Transport Modulators (pharmacology)
• Nitric Oxide (metabolism)
• Pulmonary Artery (drug effects, metabolism, physiopathology)
• Pulmonary Circulation
• Swine
• Time Factors