Statins modulate oxidized low-density lipoprotein-mediated adhesion molecule expression in human coronary artery endothelial cells: role of LOX-1.
LOX-1, a receptor for oxidized low-density lipoprotein (ox-LDL), plays a critical role in endothelial dysfunction and atherosclerosis. LOX-1 activation also plays an important role in monocyte adhesion to endothelial cells. A number of studies show that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) reduce total LDL cholesterol and exert a cardioprotective effect. We examined the modulation of LOX-1 expression and its function by two different statins, simvastatin and atorvastatin, in human coronary artery endothelial cells (HCAECs). We observed that ox-LDL (40 microg/ml) treatment up-regulated the expression of E- and P-selectins, VCAM-1 and ICAM-1 in HCAECs. Ox-LDL mediated these effects via LOX-1, since antisense to LOX-1 mRNA decreased LOX-1 expression and subsequent adhesion molecule expression. Pretreatment of HCAECs with simvastatin or atorvastatin (1 and 10 microM) reduced ox-LDL-induced expression of LOX-1 as well as adhesion molecules (all P < 0.05). A high concentration of statins (10 microM) was more potent than the low concentration (1 microM) (P < 0.05). Both statins reduced ox-LDL-mediated activation of the redox-sensitive nuclear factor-kappaB (NF-kappaB) but not AP-1. These observations indicate that LOX-1 activation plays an important role in ox-LDL-induced expression of adhesion molecules. Inhibition of expression of LOX-1 and adhesion molecules and activation of NF-kappaB may be another mechanism of beneficial effects of statins in vascular diseases.
Department of Internal Medicine, University of Arkansas for Medical Sciences, 4301 W Markham, Little Rock, AR 72205, USA.
Dayuan
D
Li
Hongjiang
H
Chen
Francesco
F
Romeo
Tatsuya
T
Sawamura
Tom
T
Saldeen
Jawahar L
JL
Mehta
D000069059:Atorvastatin; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000235:genetics*; D003331:Coronary Vessels / Q000502:physiology*; D004730:Endothelium, Vascular / Q000502:physiology*; D006538:Heptanoic Acids / Q000494:pharmacology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008077:Lipoproteins, LDL / Q000097:blood*; D016328:NF-kappa B / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology; D011973:Receptors, LDL / Q000235:genetics / Q000502:physiology*; D051131:Receptors, Oxidized LDL; D051127:Scavenger Receptors, Class E; D019821:Simvastatin / Q000494:pharmacology
D015815:Cell Adhesion Molecules; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008077:Lipoproteins, LDL; D016328:NF-kappa B; C495137:OLR1 protein, human; D011758:Pyrroles; D011973:Receptors, LDL; D051131:Receptors, Oxidized LDL; D051127:Scavenger Receptors, Class E; D000069059:Atorvastatin; D019821:Simvastatin