Lysophosphatidylcholine enhances cytokine production of endothelial cells via induction of L-type amino acid transporter 1 and cell surface antigen 4F2.
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.


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-[(14)C]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.
Takabe
Wakako
W
Laboratory for Systems Biology and Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, 4-6-1 Komaba, Meguro, Tokyo, 153-8904, Japan.
Kanai
Yoshikatsu
Y
Chairoungdua
Arthit
A
Shibata
Noriyuki
N
Toi
Sono
S
Kobayashi
Makio
M
Kodama
Tatsuhiko
T
Noguchi
Noriko
N
D000818:Animals; D001011:Aorta; D001161:Arteriosclerosis / Q000378:metabolism; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D019281:Dimerization; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology*; D027282:Fusion Regulatory Protein 1, Heavy Chain / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D027261:Fusion Regulatory Protein-1 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D027283:Large Neutral Amino Acid-Transporter 1 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015227:Lipid Peroxidation; D008077:Lipoproteins, LDL / Q000494:pharmacology; D008244:Lysophosphatidylcholines / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D014471:Umbilical Veins
D016207:Cytokines; D027282:Fusion Regulatory Protein 1, Heavy Chain; D027261:Fusion Regulatory Protein-1; D027283:Large Neutral Amino Acid-Transporter 1; D008077:Lipoproteins, LDL; D008244:Lysophosphatidylcholines; D011973:Receptors, LDL; C099252:oxidized low density lipoprotein