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.
Highlights
From the ‡Houston Veterans Administration Medical Center and the Departments of Medicine and §Pharmacology, Baylor College of Medicine, Houston, Texas 77030
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 smooth muscle cell (SMC)
The present study demonstrates that lyso-PC stimulates polyamine synthesis in vascular SMC by modulating the expression of the genes that regulate the transport and metabolism of cationic amino acids
Summary
(Received for publication, July 31, 1997, and in revised form, September 25, 1997). From the ‡Houston Veterans Administration Medical Center and the Departments of Medicine and §Pharmacology, Baylor College of Medicine, Houston, Texas 77030. The formation of putrescine from L-arginine was 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. In addition to transcellular transport, L-ornithine can be obtained from intracellular sources by endogenous synthesis In this respect, the basic amino acid L-arginine, which enters cells via the same CATs as L-ornithine, is metabolized to Lornithine and urea by arginase [27]. Lyso-PC promotes the intracellular metabolism of L-arginine to polyamines by stimulating arginase activity These lyso-PC-induced actions that promote SMC proliferation are amplified by lyso-PC inhibition of the synthesis of antiproliferative NO by inhibition of iNOS protein expression
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