Augmented endothelial uptake of oxidized low-density lipoprotein in response to endothelin-1.
Endothelin-1 (ET-1) may be involved in the development and progression of atherosclerosis. Furthermore, endothelin receptor blockade was shown to reduce the formation of atherosclerotic lesions in experimental studies. Another potent pro-atherosclerotic risk factor is oxidized low-density lipoprotein (oxLDL). Endothelial cells mediate the uptake of oxLDL by the recently identified lectin-like oxLDL receptor-1 (LOX-1), which accumulates in atherosclerotic lesions. In the present study, we analysed the effects of ET-1 on oxLDL uptake and LOX-1 expression in primary cultures of human umbilical vein endothelial cells (HUVEC). ET-1 stimulated uptake of oxLDL in HUVEC, which reached a maximum after 1 h. In further studies, we found a similar induction of LOX-1 mRNA and protein expression in response to ET-1. The augmented oxLDL uptake and the increased LOX-1 expression in response to ET-1 are mediated by the endothelin receptor B. Our data support a new pathophysiological mechanism by which locally and systemically increased ET-1 levels, e.g. in hypertensive patients, could promote LOX-1-mediated oxLDL uptake in human endothelial cells. This mechanism could promote the development and progression of endothelial dysfunction and atherosclerosis. In addition, endothelin receptor blockade could be considered as a new anti-atherosclerotic therapeutic principle.
Institute of Pathophysiology, Faculty of Medicine, Martin Luther University Halle-Wittenberg, D-06097 Halle, Germany. henning.morawietz@medizin.uni-halle.de
Henning
H
Morawietz
Nicole
N
Duerrschmidt
Bernd
B
Niemann
Jan
J
Galle
Tatsuya
T
Sawamura
Juergen
J
Holtz
D001161:Arteriosclerosis / Q000378:metabolism; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000378:metabolism*; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D011973:Receptors, LDL / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D051131:Receptors, Oxidized LDL; D051127:Scavenger Receptors, Class E; D013268:Stimulation, Chemical; D014471:Umbilical Veins
D019332:Endothelin-1; D008077:Lipoproteins, LDL; C495137:OLR1 protein, human; D012333:RNA, Messenger; D011973:Receptors, LDL; D051131:Receptors, Oxidized LDL; D051127:Scavenger Receptors, Class E; C099252:oxidized low density lipoprotein