Title: Prolonged hypoxia augments L-citrulline transport by system A in the newborn piglet pulmonary circulation.
Authors: Fike, Candice D; Sidoryk-Wegrzynowicz, Marta; Aschner, Michael; Summar, Marshall; Prince, Lawrence S; Cunningham, Gary; Kaplowitz, Mark; Zhang, Yongmei; Aschner, Judy L
Published In Cardiovasc Res, (2012 Aug 01)
Abstract: 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.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.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.
PubMed ID: 22673370
MeSH Terms: Amino Acid Transport System A/antagonists & inhibitors; Amino Acid Transport System A/metabolism*; Animals; Animals, Newborn; Biological Transport; Cells, Cultured; Chronic Disease; Citrulline/metabolism*; Disease Models, Animal; Endothelial Cells/drug effects; Endothelial Cells/metabolism*; Familial Primary Pulmonary Hypertension; Hypertension, Pulmonary/etiology; Hypertension, Pulmonary/metabolism; Hypertension, Pulmonary/physiopathology; Hypoxia/complications; Hypoxia/metabolism*; Hypoxia/physiopathology; Membrane Transport Modulators/pharmacology; Nitric Oxide/metabolism; Pulmonary Artery/drug effects; Pulmonary Artery/metabolism*; Pulmonary Artery/physiopathology; Pulmonary Circulation*; Swine; Time Factors