Angiotensin II induces LOX-1, the human endothelial receptor for oxidized low-density lipoprotein

Background-Oxidatively modified LDL (oxLDL) plays an important role in the development of atherosclerosis. OxLDL effects, eg, foam cell formation, are mediated in part by the classic scavenger receptor, whereas other effects may involve the recently cloned endothelial oxLDL receptor, LOX-1 (lectinli ke oxLDL receptor-1), which is distinct from macrophage scavenger receptors , Because the regulation of LOX-1 must still be defined, we investigated wh ether LOX-1 is regulated by the potentially proatherosclerotic stimulant an giotensin II (Ang ii). Methods and Results-Using competitive reverse transcription-polymerase chai n reaction (RT-PCR, we quantified mRNA expression of LOX-1 in primary cultu res of human umbilical vein endothelial cells (HUVECs). After treatment wit h Ang II for 3 hours (1 nmol/L to 1 mu mol/L), LOX-1 mRNA was concentration -dependently induced (from 6.9+/-1.4 to 23.1+/-5.5 relative units [RU] by 1 mu mol/L Ang II; P<0.05), The angiotensin II type I (AT(1)) receptor antag onist losartan prevented this induction. Incubation of HUVECs with Ang IT ( 100 nmol/L, 3 hours) induced LOX-1 protein expression (212+/-21% of control level: P<0.01) and uptake of 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocar bocyanine perchlorate (DiI)-labeled oxLDL(209+/-17% of control level; P<0.0 5) by an AT(1)-dependent pathway, reaching its maximum after 24 hours (680/-89%; P<0.05), In internal mammary artery biopsy samples from patients wit h or without ACE inhibitor treatment before coronary artery bypass surgery, LOX-1 mRNA was downregulated by ACE inhibition (6.4+/-2.0 versus 19.3+/-5. 9 RU; n=12 each; P<0.05), Conclusions-We conclude that LOX-1 is regulated by Ang II in vitro and in v ivo, that induction of LOX-1 is mediated by the AT(1) receptor, and that re pression of LOX-1 by long-term ACE inhibitor treatment may contribute to th e antiatherosclerotic potential of this therapy.