title: Lysophosphatidylcholine regulates cationic amino acid transport and metabolism in vascular smooth muscle cells. Role in polyamine biosynthesis.
abstract: Lysophosphatidylcholine (lyso-PC) is a major component of atherogenic lipids that stimulate vascular smooth muscle cell (SMC) proliferation. Because cationic amino acids are metabolized to growth-stimulatory polyamines, we examined whether lyso-PC regulates the transcellular transport and metabolism of cationic amino acids by vascular SMC. Treatment of SMC with lyso-PC initially (0-2 h) decreased cationic amino acid uptake, whereas longer exposures (6-24 h) progressively increased transport. Kinetic studies indicated that lyso-PC-induced inhibition was associated with a decrease in affinity for cationic amino acids, but the stimulation was mediated by an increase in transport capacity. Lyso-PC strongly induced the expression of cationic amino acid transporter-2 mRNA while modestly elevating the level of cationic amino acid transporter-1 mRNA. In addition, lyso-PC stimulated intracellular cationic amino acid metabolism by inducing ornithine decarboxylase activity and mRNA expression and also by inducing arginase activity in vascular SMC. In contrast, lyso-PC inhibited the catabolism of L-arginine to nitric oxide by blocking inducible nitric oxide synthase expression. Lyso-PC increased markedly the capacity of SMC to generate putrescine, a polyamine, from extracellular L-ornithine and L-arginine. The lyso-PC-mediated increase in the production of putrescine was reversed by NG-methyl-L-arginine, a competitive inhibitor of cationic amino acid transport, or by alpha-difluoromethylornithine, an ornithine decarboxylase inhibitor. The formation of putrescine from L-arginine was also prevented by arginase inhibitor NG-hydroxy-L-arginine. These results demonstrate that lyso-PC stimulates polyamine synthesis in vascular SMC by inducing the expression of the genes that regulate both the transport and metabolism of cationic amino acids. The actions of lyso-PC in stimulating cationic amino acid uptake and directing their metabolism to growth-stimulatory polyamines while simultaneously inhibiting the synthesis of antiproliferative NO, may contribute to lyso-PC-induced SMC proliferation and atherosclerotic lesion formation.
authors.affiliation: Houston Veterans Administration Medical Center and the Departments of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: W
authors.initials: W
authors.lastname: Durante
authors.forename: L
authors.initials: L
authors.lastname: Liao
authors.forename: K J
authors.initials: KJ
authors.lastname: Peyton
authors.forename: A I
authors.initials: AI
authors.lastname: Schafer
mesh_terms: D026923:Amino Acid Transport Systems, Basic; D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D001119:Arginase / Q000378:metabolism; D001120:Arginine / Q000378:metabolism; D001692:Biological Transport; D002352:Carrier Proteins / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D008244:Lysophosphatidylcholines / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D009952:Ornithine / Q000378:metabolism; D009955:Ornithine Decarboxylase / Q000235:genetics; D011073:Polyamines / Q000378:metabolism*; D011700:Putrescine / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats
chemical_list: D026923:Amino Acid Transport Systems, Basic; D000596:Amino Acids; D002352:Carrier Proteins; D008244:Lysophosphatidylcholines; D008565:Membrane Proteins; D011073:Polyamines; D012333:RNA, Messenger; D001120:Arginine; D009952:Ornithine; D019001:Nitric Oxide Synthase; D001119:Arginase; D009955:Ornithine Decarboxylase; D011700:Putrescine