LYSOPHOSPHATIDYLCHOLINE REGULATES CATIONIC AMINO-ACID-TRANSPORT AND METABOLISM IN VASCULAR SMOOTH-MUSCLE CELLS - ROLE IN POLYAMINE BIOSYNTHESIS

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 po lyamines, we examined whether lyso-PC regulates this transcellular tra nsport and metabolism of cationic amino acids by vascular SMC. Treatme nt of SMC with lyso-PC initially (0-2 h) decreased cationic amino acid uptake, whereas longer exposures (6-24 h) progressively increased tra nsport. Kinetic studies indicated that lyso-PC-induced inhibition was associated with a decrease in affinity for cationic amino acids, but t he 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 tran sporter-1 mRNA. In addition, lyso-PC stimulated intracellular cationic amino acid metabolism by inducing ornithine decarboxylase activity an d mRNA expression and also by inducing arginase activity in vascular S MC. In contrast, lyso-PC inhibited the catabolism of L-arginine to nit ric oxide by blocking inducible nitric oxide synthase expression. Lyso -PC increased markedly the capacity of SMC to generate putrescine, a p olyamine, from extracellular L-ornithine and L-arginine. The lyso-PC-m ediated increase in the production of putrescine was reversed by N-G-m ethyl-L-arginine, a competitive inhibitor of cationic amino acid trans port, or by alpha-difluoromethylornithine, an ornithine decarboxylase inhibitor. The formation of putrescine from L-arginine was also preven ted by arginase inhibitor NC-hydroxy-L-arginine, These results demonst rate that lyso-PC stimulates polyamine synthesis in vascular SMC by in ducing the expression of the genes that regulate both the transport an d metabolism of cationic amino acids. The actions of lyso-PC in stimul ating cationic amino acid uptake and directing their metabolism to gro wth-stimulatory polyamines while simultaneously inhibiting the synthes is of antiproliferative NO, may contribute to lyso-PC-induced SMC prol iferation and atherosclerotic lesion formation.