Abstract
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 μg/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 μM) reduced ox-LDL-induced expression of LOX-1 as well as adhesion molecules (all P < 0.05). A high concentration of statins (10 μM) was more potent than the low concentration (1 μM) (P < 0.05). Both statins reduced ox-LDL-mediated activation of the redox-sensitive nuclear factor-κB (NF-κB) 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-κB may be another mechanism of beneficial effects of statins in vascular diseases.
Footnotes
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Supported by Scientist Development Grant and Beginning grant-in-aid from the American Heart Association, a Merit Review Award from the Veterans Affairs Central Office, and a contract with the Department of Defense.
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DOI: 10.1124/jpet.102.034959
- Abbreviations:
- ox-LDL
- oxidized low-density lipoprotein
- eNOS
- endothelial nitric-oxide synthase
- AP-1
- activating protein-1
- VCAM-1
- vascular cell adhesion molecule-1
- ICAM-1
- intercellular adhesion molecule-1
- NF-κB
- nuclear factor-κB
- HCAECs
- human coronary artery endothelial cells
- PCR
- polymerase chain reaction
- Received February 18, 2002.
- Accepted March 27, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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