on June 3, 2004
Published online before print June 3, 2004, doi: 10.1161/01.ATV.0000134377.17680.26
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Submitted on April 19, 2004
Accepted on May 17, 2004
Lysophosphatidylcholine Enhances Cytokine Production of Endothelial Cells via Induction of L-Type Amino Acid Transporter 1 and Cell Surface Antigen 4F2
Wakako Takabe ;
From the Laboratory for Systems Biology and Medicine (W.T., T.K., N.N.), RCAST, The University of Tokyo, Japan; Chugai Pharmaceutical Co Ltd (W.T.), Shizuoka, Japan; the Department of Pharmacology and Toxicology (Y.K., A.C.), Kyorin University School of Medicine, Tokyo, Japan; and the Departments of Pathology (N.S., M.K.) and Neurology (S.T.), Tokyo Women’s Medical University, Tokyo, Japan.
* To whom correspondence should be addressed. E-mail: noguchi{at}lsbm.org.
Objective--A diverse range of lipid oxidation products detected in oxidized low-density lipoprotein (oxLDL) and atherosclerotic lesions are capable of eliciting biological responses in vascular cells. We performed DNA microarray experiments to explore novel responses of human umbilical vein endothelial cells (HUVECs) to oxLDL and its components.
Methods and Results--cDNA microarray analysis showed that oxLDL, lysophosphatidylcholine (LysoPC), 4-hydroxy-2-nonenal, and oxysterols altered gene expression specifically, but some genes were commonly induced in HUVECs. Solute carrier family 3 member 2 and family 7 member 5, encoding the heavy chain of the cell surface antigen 4F2 (4F2hc) and the L-type amino acid transporter 1 (LAT1), respectively, were induced by oxLDL and many oxidation products. LAT1 requires 4F2hc to form a heterodimeric functional complex to transport neutral amino acids into the cell. LysoPC increased membrane protein levels of LAT1 confirmed by Western blot analysis and also uptake of L-[14C]leucine, which was inhibited by a competitive inhibitor for LAT1. The release of interleukin 6 (IL-6) and IL-8 was increased in LysoPC-treated cells and was attenuated by the LAT1 inhibitor.
Conclusions--These findings suggest that an increase in uptake of neutral amino acids induced by LysoPC results in enhancement of inflammatory responses of endothelial cells. cDNA microarray analysis led us to a novel finding that oxLDL and its components such as LysoPC induced amino acid transporter expression in HUVECs, resulting in enhancement of inflammatory cytokine release, which was supposed to play an important role in atherogenesis.
Key words: amino acid transporter • atherosclerosis • cytokine • HUVEC • LysoPC
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