Detrimental effect of oxidized LDL on endothelial arginine metabolism and transportation.
The action of oxidatively modified low-density lipoprotein on vascular endothelial cells has been proposed to be a crucial process leading to endothelial dysfunction and atherogenesis. However, the biochemical mechanism for such action is not clear. We have previously shown that arginine uptake and metabolism are major determinants of endothelial function in heart failure and hypertension. In the present study we therefore aimed to assess the effects of oxidized LDL, a major pro-atherogenic molecule, on endothelial l-arginine metabolism and its uptake. Endothelial cells were exposed to oxidized LDL or native LDL for 24h, and the resultant effects on (1) the intracellular content of arginine and its major metabolites including citrulline, N(G)-hydroxy-l-arginine, asymmetric dimethylarginine, symmetric dimethylarginine and ornithine, (2) [3H]-l-arginine uptake and, (3) the pattern of distribution of cationic amino acid transporter 1, the principal l-arginine transporter, by confocal microscopy. Oxidized LDL (100 microg/mL) reduced intracellular arginine and N(G)-hydroxy-l-arginine contents by 56 and 71% (P<0.05), respectively, with a concomitant 205% increase in ADMA (P<0.05). In conjunction, oxidized LDL reduced endothelial uptake of [3H]-arginine by 60%. Furthermore, incubation of endothelial cells with oxLDL led to internalization of cationic amino acid transporter 1. We demonstrate a novel mechanism, reduced l-arginine transport, by which oxidized LDL impairs the ability of the endothelium to generate nitric oxide.
Zhang
Wei-Zheng
WZ
Wynn Department of Metabolic Cardiology, Baker Heart Research Institute, PO Box 6492, St. Kilda Road Central, Melbourne, VIC 8008, Australia. weizzhang@hotmail.com
Venardos
Kylie
K
Finch
Samara
S
Kaye
David M
DM
D001120:Arginine / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects; D027201:Cationic Amino Acid Transporter 1 / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D003208:Concanavalin A / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism
D027201:Cationic Amino Acid Transporter 1; D008077:Lipoproteins, LDL; D012333:RNA, Messenger; C099252:oxidized low density lipoprotein; D003208:Concanavalin A; D001120:Arginine; D002784:Cholesterol