Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:1116-1122
© 2000 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Upregulation of Endothelial Receptor for Oxidized LDL (LOX-1) by Oxidized LDL and Implications in Apoptosis of Human Coronary Artery Endothelial Cells
Evidence From Use of Antisense LOX-1 mRNA and Chemical Inhibitors
From the Departments of Medicine and Physiology, University of Florida and VA Medical Center, Gainesville.
Correspondence to J.L. Mehta, MD, PhD, Department of Medicine, University of Florida College of Medicine, 1600 Archer Rd, PO Box 100277 JHMHC, Gainesville, FL 32610. E-mail mehta{at}medmac.ufl.edu
Abstract—A specific lectinlike
endothelial receptor for oxidized low density
lipoprotein (LOX-1), distinct from the scavenger receptor in
monocytes/macrophages, has been identified and cloned. In this
study, we examined the regulation of LOX-1 by oxidized low density
lipoprotein (ox-LDL) and determined the role of LOX-1 in
ox-LDL–induced apoptosis of cultured human coronary
artery endothelial cells (HCAECs). Incubation of HCAECs
with ox-LDL (40 µg/mL), but not native LDL, for 24 hours markedly
increased LOX-1 expression (mRNA and protein). After 48 hours of
preincubation of HCAECs with a specific antisense to LOX-1 mRNA
(antisense LOX-1), ox-LDL–mediated upregulation of LOX-1 was
suppressed (P<0.01). In contrast, treatment of HCAECs
with sense LOX-1 had no effect. Ox-LDL also induced apoptosis
(determined by terminal deoxynucleotidyl
transferase–mediated dUTP nick end-labeling and DNA laddering) of
HCAECs in a concentration- and time-dependent fashion. LOX-1 played an
important role in ox-LDL–mediated apoptosis of HCAECs because
antisense LOX-1 inhibited this effect of ox-LDL. Polyinosinic acid and
carrageenan, 2 different chemical inhibitors of LOX-1, also
decreased ox-LDL–mediated apoptosis of HCAECs. Nuclear factor
(NF)-
B was markedly activated in ox-LDL–treated HCAECs. The
critical role of NF-B activation became evident in experiments with
antisense LOX-1, which abolished ox-LDL–mediated NF-B activation.
In this process, an NF-B inhibitor, caffeic acid
phenethyl ester, also inhibited ox-LDL–mediated apoptosis of
HCAECs. These findings indicate that ox-LDL upregulates its own
endothelial receptor. Ox-LDL–induced apoptosis
is mediated by the action of LOX-1. In this process, NF-B activation
may play an important role as a signal transduction mechanism.
Key Words: apoptosis • endothelial cells • LOX-1 • nuclear factor-B • oxidized LDL
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