© 1999 American Heart Association, Inc.
Original Contributions |
Induction of Monocyte Binding to Endothelial Cells by MM-LDL
Role of Lipoxygenase Metabolites
Presented in part as an abstract at the Joint Annual Meeting of the American Society for Biochemistry, the American Society for Investigative Pathology, and the American Association of Immunologists, New Orleans, La, 1996.
From the Department of Medicine (Cardiology) (H.M.H., J.I.G., J.N.W., J.A.B.), Physiology (J.N.W.), and Pathology and Laboratory Medicine (N.L., M.F., J.A.B.), Cardiovascular Research Laboratory (H.M.H., J.I.G., J.N.W.), University of California at Los Angeles; and City of Hope National Medical Center (R.N., J.L.N.), Duarte, Calif.
Correspondence to Henry M. Honda, MD, UCLA School of Medicine, CHS 47-123, 10833 Le Conte Ave, Los Angeles, CA 90095-1679. E-mail hhonda{at}mednet.ucla.edu
Abstract—Treatment of human
aortic endothelial cells (EC) with minimally oxidized
LDL (or minimally modified LDL, MM-LDL) produces a specific pattern of
endothelial cell activation distinct from that produced
by LPS, tumor necrosis factor-
, and interleukin-1, but similar to
other agents that elevate cAMP. The current studies focus on the signal
transduction pathways by which MM-LDL activates EC to bind
monocytes. We now demonstrate that, in addition to an elevation of
cAMP, lipoxygenase products are necessary for the
MM-LDL response. Treatment of EC with inhibitors of the
lipoxygenase pathway, 5,8,11,14-eicosatetraynoic acid
(ETYA) or cinnamyl-3,4-dihydroxy--cyanocinnamate (CDC), blocked
monocyte binding in MM-LDL-treated EC (MM-LDL=118±13%;
MM-LDL+ETYA=33±4%; MM-LDL+CDC=23±4% increase in monocyte binding)
without reducing cAMP levels. To further investigate the role of the
lipoxygenase pathway, cellular phospholipids were
labeled with arachidonic acid. Treatment of cells for 4
hours with 50 to 100 µg/mL MM-LDL, but not native LDL, caused a 60%
increase in arachidonate release into the medium and
increased the intracellular formation of 12(S)-HETE (
100%
increase). There was little 15(S)-HETE present, and no increase in
its levels was observed. We demonstrated that 12(S)-HETE reversed the
inhibitory effect of CDC. We also observed a 70% increase
in the formation of 11,12-epoxyeicosatrienoic acid (11,12-EET) in cells
treated with MM-LDL. To determine the mechanism of
arachidonate release induced by MM-LDL, we examined the
effects of MM-LDL on intracellular calcium levels. Treatment of EC with
both native LDL and MM-LDL caused a rapid release of intracellular
calcium from internal stores. However, several pieces of evidence
suggest that calcium release alone does not explain the increased
arachidonate release in MM-LDL-treated cells. The
present studies suggest that products of
12-lipoxygenase play an important role in MM-LDL action
on the induction of monocyte binding to EC.
Key Words: intracellular calcium • lipoxygenase inhibitors • minimally modified LDL • endothelial cells
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