(The FASEB Journal. 2001;15:2073-2084.)
© 2001 FASEB
Oxidized LDL and HDL: antagonists in atherothrombosis
ANN MERTENS and
PAUL HOLVOET1
Center for Experimental Surgery and Anesthesiology, Katholieke Universiteit Leuven, Belgium
1Correspondence: Center for Experimental Surgery and Anesthesiology (CEHA), Katholieke Universiteit Leuven, Campus Gasthuisberg, O&N, Herestraat 49, B-3000 Leuven, Belgium. E-mail: paul.holvoet{at}med.kuleuven.ac.be
 |
ABSTRACT
|
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Increased LDL oxidation is associated with coronary artery disease. The
predictive value of circulating oxidized LDL is additive to the Global
Risk Assessment Score for cardiovascular risk prediction based on age,
gender, total and HDL cholesterol, diabetes, hypertension, and smoking.
Circulating oxidized LDL does not originate from extensive metal
ion-induced oxidation in the blood but from mild oxidation in the
arterial wall by cell-associated lipoxygenase and/or myeloperoxidase.
Oxidized LDL induces atherosclerosis by stimulating monocyte
infiltration and smooth muscle cell migration and proliferation. It
contributes to atherothrombosis by inducing endothelial cell apoptosis,
and thus plaque erosion, by impairing the anticoagulant balance in
endothelium, stimulating tissue factor production by smooth muscle
cells, and inducing apoptosis in macrophages. HDL cholesterol levels
are inversely related to risk of coronary artery disease. HDL prevents
atherosclerosis by reverting the stimulatory effect of oxidized LDL on
monocyte infiltration. The HDL-associated enzyme paraoxonase inhibits
the oxidation of LDL. PAF-acetyl hydrolase, which circulates in
association with HDL and is produced in the arterial wall by
macrophages, degrades bioactive oxidized phospholipids. Both enzymes
actively protect hypercholesterolemic mice against atherosclerosis.
Oxidized LDL inhibits these enzymes. Thus, oxidized LDL and HDL are
indeed antagonists in the development of cardiovascular
disease.—Mertens, A., Hobvoet, P. Oxidized LDL and HDL: antagonists in
atherothrombosis.
Key Words: atherosclerosis • oxidation • lipoproteins • coronary artery disease
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INTRODUCTION
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IN THIS REVIEW we focus on the presence of different
forms of oxidatively modified LDL in the circulation and their relation
to cardiovascular disease. We discuss cellular mechanisms of oxidative
modification of LDL, the effects of oxidized low density lipoproteins
(LDL) on endothelial cells, and their interaction with
monocytes/leukocytes and platelets in vitro and in vivo.
The inverse relation between high density lipoprotein (HDL) cholesterol
and risk of cardiovascular disease is well established. The protective
effect of HDL has been attributed to its role in reverse cholesterol
transport. We focus here on the anti-inflammatory and antioxidative
effects of HDL. The relationship between HDL-associated antioxidative
enzymes (paraoxonase and PAF-acetylhydrolase) and the oxidation of
lipoproteins in vivo is discussed.
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LDL OXIDATION
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Biochemical composition of LDL
The central core of LDL particles contains 1600 molecules of
cholesterol ester and 170 molecules of triglycerides. It is surrounded
by a monolayer of 700 phospholipid molecules, consisting primarily of
lecithin, small amounts of sphingomyelin and lysolecithin, and 600
molecules of cholesterol (1)
. Embedded in the outer layer
is one apoB-100 molecule. About half of the fatty acids in LDL are
polyunsaturated fatty acids (PUFAs), mainly linoleic acid
with minor amounts of arachidonic acid and docosahexaenoic acid. These
PUFAs are protected against free radical attack and oxidation by
antioxidants, primarily 
-tocopherol (
six molecules per LDL
particle), with minor amounts of 
-tocopherol, carotenoids,
cryptoxanthin, and ubiquinol-10 (2)
. The amount of PUFAs
and antioxidants varies significantly within individuals, resulting in
a great variation in LDL oxidation susceptibility.
Mechanisms of LDL oxidation
LDL can be oxidized by metal ions, lipoxygenases,
myeloperoxidase, and reactive nitrogen species (Fig. 1
).
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Figure 1. Mechanisms of LDL oxidation. In vitro oxidation of LDL by metal ions
occurs in three phases: an initial lag phase (consumption of endogenous
antioxidant), a propagation phase (rapid oxidation of unsaturated fatty
acids to lipid hydroperoxides), and a decomposition phase (formation of
reactive aldehydes). These aldehydes react with lysine residues in
apoB-100, resulting in oxidized LDL. NO inhibits copper-mediated
oxidation. The metal ion-dependent enzyme lipoxygenase converts
polyunsaturated fatty acids into lipid hydroperoxides and thereby
oxidizes LDL. Activated macrophages secrete myeloperoxidase, which
generates reactive species, thereby oxidizing protein and lipid
moieties of LDL. NO is converted under aerobic conditions to nitrite.
Nitrite inhibits the myeloperoxidase-mediated oxidation of LDL.
Finally, oxidized LDL is interacting with scavenger receptors present
on endothelial cells, macrophages, and smooth muscle cells.
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Metal ions
In vitro oxidation of LDL by metal ions (e.g.,
Cu2+) occurs in three phases: an initial lag
phase (consumption of endogenous antioxidants), a propagation phase
(rapid oxidation of unsaturated fatty acids to lipid hydroperoxides),
and a decomposition phase (hydroperoxides are converted to reactive
aldehydes, e.g., malondialdehyde, 4-hydroxynonenal). Interaction of
these aldehydes with positively charged 
-amino groups of lysine
residues renders the LDL more negatively charged, resulting in
decreased affinity for the LDL receptor and increased affinity for
scavenger receptors (Fig. 1)
.
It is unlikely that free metal ions are responsible for in vivo LDL
oxidation. There is no convincing evidence for free metal ion in plasma
or the arterial wall. There is also no significant accumulation of
o-tyrosine and m-tyrosine, typical oxidation products of free
metal ion, in fatty streaks or intermediate atherosclerotic lesions
(3)
.
Lipoxygenases
15-Lipoxygenase, produced by endothelial cells and
monocytes/macrophages, converts polyunsaturated fatty acids into lipid
hydroperoxides and thereby oxidizes LDL (Fig. 1)
. Lipoxygenase
inhibitors block in vitro oxidation of LDL by these cells
(4
5
6)
. Overexpression of 15-lipoxygenase in vascular
endothelium accelerates early atherosclerosis in LDL receptor-deficient
mice (7)
. Disruption of the 12/15-lipoxygenase genes
diminishes atherosclerosis in apoE knockout mice (8)
in
the absence of changes in cholesterol, triglyceride, and lipoprotein
levels.
Hyperglycemia causes up-regulation of 12-lipoxygenase (9)
.
Increased production of 12-hydroxyeicosatetraenoic acid, the
lipoxygenase metabolite of arachidonic acid, results in enhanced
adhesion of monocytes to endothelium, a key early event in
atherogenesis.
Myeloperoxidase
Activated phagocytes secrete myeloperoxidase that generates
reactive species including hypochlorous acid (HOCl), chloramines,
tyrosyl radicals, and nitrogen dioxide (NO2).
These reactive species oxidize antioxidants, lipids, and protein of LDL
(10)
(Fig. 1)
. Reactive nitrogen species generated by the
myeloperoxidase-H2O2-NO2
system of monocytes convert LDL into an atherogenic form that is avidly
taken up and degraded by macrophages, leading to foam cell formation
(11)
.
Monoclonal antibodies raised against HOCl-modified LDL that do not
cross react with other LDL modifications (copper-oxidized LDL,
4-hydroxynonenal-LDL, malondialdehyde-LDL, and glycated LDL) detect
HOCl-modified LDL in the neighborhood of endothelial cells and
monocyte/macrophages in human atherosclerotic lesions
(12)
.
Activated human neutrophils generate p-hydroxyphenyl
acetaldehyde (pHA), the major product of L-tyrosine oxidation by the
myeloperoxidase-HOCl-H2O2
system. The concentration of pHA-modified phospholipid in LDL isolated
from human atherosclerotic lesions is markedly increased compared with
circulating LDL (13)
. Sugiyama et al. (14)
recently identified granulocyte macrophage colony-stimulating factor as
an endogenous regulator of myeloperoxidase expression in human
atherosclerosis. Furthermore, increased numbers of
myeloperoxidase-expressing macrophages were demonstrated in eroded or
ruptured plaques causing acute coronary syndromes, suggesting a role
for myeloperoxidase-expressing macrophages in human atheroma
complications. In contrast, disruption of the myeloperoxidase gene in
LDL receptor-deficient mice resulted in increased atherosclerosis
(15)
. This study thus suggested an important distinction
between mouse and human atherosclerosis with regard to the potential
involvement of myeloperoxidase in protein oxidation.
Reactive nitrogen species
Nitric oxide (NO) is a free radical released by various vascular
cells (16)
. It inhibits copper-mediated oxidation
(17)
as well as cell-mediated oxidation of LDL
(18)
(Fig. 1)
. NO is converted under aerobic conditions to
nitrite, and low concentrations of nitrite (12 µM compared with
physiological concentrations of up to 200 µM) inhibit
myeloperoxidase-mediated oxidation of LDL (19)
. NO also
acts as an antioxidant by scavenging alkoxyl and peroxyl radicals.
The NO radical interacts with superoxide anion to form the
peroxynitrite anion (ONOO-) that decomposes into
the hydroxyl radical OH., which oxidizes LDL
(20)
. Peroxynitrite also oxidizes tetrahydrobiopterin, a
critical cofactor for NO synthase (NOS), and thereby decreases NO
production (21)
. Expression of inducible NOS, associated
with increased peroxynitrite production, resulted in increased
apoptotic cell death in atheromatous plaques of human coronary arteries
(22)
. Thus, when NO is in excess of surrounding oxidants,
lipid oxidation and monocyte margination into the vascular wall are
attenuated, producing anti-atherogenic effects. However, when oxidant
defenses become depleted or endogenous tissue rates of oxidant
production are accelerated, NO gives rise to secondary oxidizing
species that increase membrane and lipoprotein lipid oxidation as well
as foam cell formation in the vasculature (23)
.
Biochemical composition of oxidized LDL
We have isolated oxidized LDL from the plasma of patients with
coronary artery disease. It was characterized by a 1.3-fold higher
electrophoretic mobility on agarose gels compared with native LDL
fractions of the same patients, a 75% reduction of the arachidonate
levels and an 80% reduction of the linoleic acid levels. The fractions
of aldehyde-substitution of lysine residues was 30–40% of that in
standard preparations of in vitro oxidized LDL, indicating that between
60 and 90 lysine residues in the apoB-100 moiety of oxidized LDL were
substituted. These characteristics suggested that in vivo oxidized LDL
does not originate from extensive metal ion-induced oxidation of LDL,
but that it is most likely generated by cell-associated oxidative
enzymatic activity in the arterial wall (24
, 25)
.
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OXIDIZED LDL IN CARDIOVASCULAR DISEASE
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Until recently, methods for direct measurement of oxidized LDL in
blood were lacking. Therefore, indirect methods have been used to study
the association between oxidized LDL and cardiovascular disease. An
indirect indication of in vivo oxidation of LDL is the increase of the
titer of autoantibodies against neo-epitopes in oxidized LDL. Salonen
et al. (26)
reported a correlation between titers of
autoantibodies against oxidized LDL and the progression of carotid
atherosclerosis. However, data on the relation between autoantibody
titer and coronary or carotid atherosclerosis are not consistent
(27
28
29
30
31)
, possibly due to assay divergences in the
different studies. For example, there is no agreement about how the
oxidized LDL used in the different immunoassays should be generated in
vitro and what its composition should be. Furthermore, most of the
studies evaluating the clinical significance of antibodies against
oxidized LDL are cross-sectional and only a few follow-up studies are
published. The role of humoral immune reactions in atherogenesis is not
clear, and may be different in patient groups as well as at different
stages of the disease. Thus, there is need for well-controlled
follow-up studies with standardized assays to determine the prognostic
value of antibodies against oxidized LDL.
Sensitive assays to measure circulating LDL are now available. We have
raised the monoclonal antibody mAb-4E6 against a neo-epitope in the
aldehyde-substituted apolipoproteinB-100 moiety of oxidized LDL
(32)
. A mAb-4E6-based competition ELISA has been used to
study the association between circulating oxidized LDL and coronary
artery disease (CAD) (24
, 25)
. At a cutoff value of 2.30
mg/dl, the sensitivity of our assay for CAD was 76% with a specificity
of 90%. The American Heart Association and the American College of
Cardiology have introduced the Global Risk Assessment Score for
Cardiovascular Risk prediction (GRAS) (33)
. It is based on
the Framingham risk factors age, total cholesterol, HDL cholesterol,
systolic blood pressure, diabetes mellitus, and smoking. The predictive
value of circulating oxidized LDL was additive to that of GRAS; 94% of
subjects with high circulating oxidized LDL and high GRAS had CAD
(34)
. These data indicate that circulating oxidized LDL is
a useful marker for identifying patients with CAD. Meanwhile, two other
groups have confirmed our results using an immunoassay for oxidized LDL
based on a monoclonal antibody raised against oxidized products of
phosphatidylcholine (35
, 36)
. We recently demonstrated
that plasma levels of circulating oxidized LDL predict the development
of transplant coronary artery disease in heart transplant patients
(37)
, suggesting that oxidized LDL plays an active role in
the development of CAD.
Studies with stable isotopes have suggested that oxidation of
apolipoprotein B-100 (apoB-100) in circulating LDL is related to LDL
residence time (38
, 39)
. The longer the residence time of
LDL is, the longer the exposure of its apoB-100 moiety to the attack of
reactive oxygen species. Especially small, dense LDL
(LDL2 and LDL3) has a
reduced affinity for the hepatic LDL receptor (40)
, a
longer residence time, and therefore greater susceptibility to
oxidation (41)
. Four recent prospective reports provided
further support for a critical role of small, dense LDL particles in
the etiology of atherosclerosis (42
43
44
45)
.
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REGULATION OF EXPRESSION OF SCAVENGER RECEPTORS FOR OXIDIZED LDL
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Interaction of modified LDL with scavenger receptors (class A,
class B, LOX-1) induces rapid and unregulated uptake of the modified
LDL leading to massive cholesterol accumulation (46)
.
Scavenger receptor class A (SR-A) regulates the development of
atherosclerotic lesions through uptake of oxidized LDL by macrophages.
The expression of SR-A in vitro is related to the state of cell
differentiation. Freshly isolated human monocytes have minimal SR-A
activity, but differentiated macrophages express SR-A activity.
Expression of SR-A in human monocytes is induced by macrophage
colony-stimulating factor (M-CSF) in human monocytes (47)
,
and inhibited by interferon gamma (IFN-) (48)
,
transforming growth factor beta (TGF-ß) (49)
, tumor
necrosis factor alpha (TNF-) (50)
, and peroxisome
proliferator-activated receptor gamma ligands (51)
, such
as fatty acids and prostaglandin D2 metabolites. IFN- and TNF-
increase SR-A expression in smooth muscle cells (52
, 53)
.
The reason for the opposite effects of these cytokines on SR-A
expression in smooth muscle cells vs. macrophages is unclear.
CD36 (a class B scavenger receptor) is a second oxidized LDL receptor
present on platelets, monocytes, endothelial cells, and adipocytes. The
affinity of oxidized LDL for CD36 is about threefold greater than that
of native LDL (54)
. CD36 is the major receptor responsible
for high-affinity recognition of oxidized LDL by macrophages
(55)
. Macrophages of CD36-apoE double knockout mice
accumulate 60% less copper-oxidized LDL and LDL modified by
monocyte-derived reactive nitrogen species than macrophages from apoE
knockout mice (56)
. These results suggest that blockade of
CD36 may be protective even in more extreme proatherogenic
circumstances.
Mouse macrosialin or its human homologue CD68 is a third oxidized LDL
receptor that is expressed only in macrophages and dendrite cells.
Yoshida et al. (57)
showed that oxidized LDL induces
expression of macrosialin and other scavenger receptors. Extensively
oxidized LDL induced more macrosialin expression than mildly oxidized
LDL, but the effect of pretreatment with mildly oxidized LDL on
internalization and degradation of oxidized LDL is much greater than
with extensively oxidized LDL. The generation of macrosialin knockout
mice will teach us more about the role of the macrosialin receptor in
atherosclerosis.
The expression of the lectin-like oxidized LDL receptor or LOX-1 in
vascular endothelial cells (58)
is induced by TNF- and
shear stress (59
, 60)
. Uptake of oxidized LDL via LOX-1 in
vascular endothelial cells in vivo may not result in massive lipid
accumulation, but may cause endothelial activation and/or dysfunction.
Superoxide anions, hydrogen peroxide, and homocystein also increase
LOX-1 expression (61)
. Different groups have shown that
expression of LOX-1 can also be induced in smooth muscle cells and
macrophages (62
, 63)
. TGF-ß appears to be one of the key
regulators of scavenger receptor expression (SR-A, CD36 and LOX-1)
(64)
.
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BIOLOGICAL ACTIVITIES OF OXIDIZED LDL
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Effect of oxidized LDL on monocyte infiltration
Adhesion and infiltration of macrophages into the arterial wall
contributes to fatty streak formation. A triggering event in the
development of fatty streaks is accumulation, retention and oxidation
of LDL into minimally oxidized LDL (MM-LDL). MM-LDL induces endothelium
to express adhesion molecules for monocytes, intercellular adhesion
molecule 1 (ICAM-1) and vascular adhesion molecule (VCAM-1)
(65)
(Fig. 2
A).
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Figure 2. A) Effect of OxLDL on monocyte infiltration. Adhesion
and infiltration of macrophages contributes to fatty streak formation.
MM-LDL induces endothelium to express adhesion molecules for monocytes,
ICAM-1, VCAM-1, E-selectin, and fibronectin. MM-LDL induces expression
of PLA2 and MPO in macrophages. PLA2 liberates
polyunsaturated fatty acids from HDL and LDL and increases the
formation of oxidized phospholipids. OxLDL stimulates the endothelium
to secrete MCP-1, which induces infiltration of monocytes into the
endothelial space. Macrophages secrete M-CSF, thereby stimulating
macrophage proliferation. Interaction of OxLDL with SR induces
unregulated uptake of modified LDL leading to massive cholesterol
accumulation and formation of foam cells, finally resulting in
apoptotic macrophages triggering thrombosis. B) Effect
of OxLDL on smooth muscle cell migration and proliferation. OxLDL
induces migration of smooth muscle cells by increasing the expression
of PDGF by endothelial cells, smooth muscle cells, and macrophages.
OxLDL stimulates smooth muscle cell proliferation by inducing
expression of bFGF by endothelial cells and smooth muscle cells. MM-LDL
and TxA2 released by aggregating platelets have a
synergistic interaction on smooth muscle cell proliferation.
C) Effect of OxLDL on thrombosis. OxLDL stimulates
platelet adhesion and aggregation by decreasing endothelial production
of NO, increasing PGI2 production, and stimulating the
synthesis of prostaglandins and prostaglandin precursors. OxLDL
enhances the procoagulant activity of endothelium by inducing the
release of TF by endothelial cells and smooth muscle cells. TF is a
cofactor of factor VIIa that activates factors IX and X, resulting in
thrombin formation. OxLDL reduces the fibrinolytic activity of
endothelium by decreasing secretion of tPA and increasing the release
of PAI-1. OxLDL contributes to apoptosis in endothelial cells, smooth
muscle cells, and foam cells and thereby induces thrombosis. Increased
shear stress and increased plasma levels of homocystein also induce
endothelial dysfunction.
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Active compounds in MM-LDL are phospholipid auto-oxidation
products such as
1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine
(POVPC),
1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphocholine
(PGPC), and 1-palmitoyl-2-epoxyisoprostane
E(2)-sn-glycero-3-phosphocholine (PEIPC) (66
, 67)
. Pretreatment of endothelial cells with platelet-activating
factor (PAF) receptor antagonists prevented their activation with POVPC
and PEIPC but not with PGPC, suggesting a role of the PAF receptor in
POVPC and PEIPC but not in PGPC-induced activation. Whereas POVPC
induces only monocyte binding, PGPC induces both monocyte and
neutrophil adhesion. At concentrations equal to those present in
MM-LDL, POVPC inhibits PGPC-induced adhesion of neutrophils
(68)
. MM-LDL also promotes monocyte proliferation and
differentiation into macrophages by inducing M-CSF expression by
endothelial cells (69)
.
MM-LDL becomes extensively oxidized LDL because of the action of
sphingomyelinase, which induces LDL retention and aggregation
(70)
, and of myeloperoxidase and secretory phospholipase
A2 (71)
. Polyunsaturated free fatty
acids liberated from LDL and HDL by secretory phospholipase
A2 (sPLA2) increase the
formation of oxidized phospholipids that stimulate
monocyte–endothelial interactions and atherosclerosis in transgenic
mice (72)
. Upston et al. (73)
demonstrated
that phospholipase A2 significantly enhanced the
accumulation of cholesterol ester hydroperoxides induced by
15-lipoxygenase. Furthermore, MM-LDL induces expression of
sPLA2 in monocyte-derived macrophages
(74)
(Fig. 2A
).
Oxidized LDL stimulates endothelium to secrete monocyte chemotactic
protein 1 (MCP-1), which induces the infiltration of monocytes into the
subendothelial space (75)
. Li and Mehta (76)
demonstrated that interaction of oxidized LDL with LOX-1 is required
for the oxidized LDL-mediated up-regulation of MCP-1 by human coronary
artery endothelial cells (Fig. 2A
). Because oxidized LDL is
a potent inhibitor of macrophage motility, it may promote macrophage
retention in the arterial wall.
Effect of oxidized LDL on smooth muscle cell migration and
proliferation
During atherogenesis, smooth muscle cells undergo a phenotypic
modification to a synthetic state, allowing them to migrate from the
intima to the media where they are proliferating and secreting growth
factor, extracellular matrix glycoprotein, and metalloproteinases
(77
, 78)
. This leads to fibrous plaque formation. Oxidized
LDL induces migration of smooth muscle cells by increasing the
expression of platelet-derived growth factor (PDGF) by endothelial
cells, smooth muscle cells, and macrophages (79
80
81)
.
Oxidized LDL also stimulates smooth muscle cell proliferation by
inducing expression of basic fibroblast growth factor (bFGF) by
endothelial cells and smooth muscle cells (82)
. A
synergistic interaction between MM-LDL and thromboxane
A2 on smooth muscle cell proliferation has been
demonstrated (83)
. Thromboxane A2 is
released by aggregating platelets at sites of endothelial injury (Fig. 2B
).
Effect of oxidized LDL on vasoreactivity
Intimal thickening is caused by accumulation of foam cells and by
smooth muscle cell migration and proliferation. It results in reduction
of arterial lumen, which is exacerbated by impairment of the
vasodilator capacity of the artery. Oxidized LDL may induce
vasoconstriction through inhibition of NO production (84
, 85)
and stimulation of expression of endothelin
(86)
(Fig. 2C
).
Effect of oxidized LDL on apoptosis
Apoptosis in endothelial and smooth muscle cells is contributing
to plaque rupture (87)
. The apoptotic effect of oxidized
LDL on endothelial cells could be attributed to oxidation products of
phosphatidylcholine (88)
or to oxysterols.
Oxysterol-mediated apoptosis induces activation of MAP and Jun/SAP
kinases and increased p53 production (89
, 90)
. An
irreversible caspase inhibitor decreased oxidized LDL-induced apoptosis
in endothelial cells (91)
.
Effect of oxidized LDL on thrombosis
Endothelial dysfunction is associated with enhanced platelet
adhesion, increased procoagulant activity, and impaired fibrinolysis
(92)
. Oxidized LDL stimulates platelet adhesion and
aggregation by decreasing endothelial production of NO, increasing
prostacyclin (PGI2) production (93
, 94)
, and stimulating the synthesis of prostaglandins and
prostaglandin precursors (95)
(Fig. 2C
).
Oxidized LDL enhances the procoagulant activity of endothelium by
inducing the release of tissue factor (TF) by endothelial cells and
smooth muscle cells (96
, 97)
. TF is a cofactor of factor
VIIa that activates factors IX and X, resulting in thrombin formation.
Oxidized LDL also stimulates coagulation by reducing thrombomodulin
transcription (TM) (98)
, suppressing protein C activation
(99)
, and modulating tissue factor pathway inhibitor
(100)
.
Oxidized LDL reduces the fibrinolytic activity of endothelium by
decreasing secretion of tissue-type plasminogen activator (tPA) and
increasing release of plasminogen activator inhibitor 1 (PAI-1)
(101
102
103)
.
Oxidized LDL may also contribute to plaque disruption and/or vascular
remodeling by increasing expression of metalloproteinase 9 (MMP-9) and
decreasing expression of its tissue inhibitor TIMP-1 by
monocytes/macrophages (104)
.
|
HDL IN CARDIOVASCULAR DISEASE
|
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The Framingham Heart Study (105)
demonstrated that
high density lipoprotein cholesterol (HDL-C) is the most potent lipid
predictor of coronary artery disease risk in men and women > 49
years of age. Every 1 mg/dl increment in HDL-C is associated with a 2%
decreased risk of coronary artery disease in men and a 3% decreased
risk in women.
In the Veterans Affairs HDL Intervention Trial (VA-HIT)
(106)
, subjects were randomized to gemfibrozil or placebo.
HDL-C increased by 6% on treatment. Total cholesterol and
triglycerides decreased by 4% and 31%, respectively. There was no
change in LDL-C levels. This change in lipid was associated with a
cumulative reduction in the trial primary end points: all cause
mortality and nonfatal myocardial infarction. A significant reduction
in secondary end points, including death from coronary artery disease,
nonfatal myocardial infarction, stroke, transient ischemic attack, and
carotid endarterectomy, was associated with the increase in HDL-C. In
VA-HIT, for every 1% increase in HDL-C, there was a 3% reduction in
death or myocardial infarction, a therapeutic benefit that eclipses the
benefit associated with LDL-C reduction. Triglyceride levels were not
predictive of clinical events.
HDL-C is also an important predictor of survival in men after coronary
artery bypass graft surgery. One-third fewer patients survive at 15
years if their HDL-C levels are 
35 mg/dl (107)
.
|
EFFECT OF HDL ON LDL OXIDATION
|
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Navab et al. (108
, 109)
have proposed that
biologically active lipids in LDL are formed in a series of three
steps. The first step is the seeding of LDL with products of the
metabolism of linoleic acid and arachidonic acid as well as with
hydroperoxides. The second step is trapping LDL in the subendothelial
space and the accumulation in LDL of additional reactive oxygen species
derived from artery wall cells. The third step is the nonenzymatic
oxidation of LDL phospholipids that occurs when a certain threshold of
reactive oxygen species is reached, resulting in the formation of
specific oxidized phospholipids that induce monocyte binding,
chemotaxis, and differentiation into macrophages.
Normal HDL and its major protein, apolipoprotein AI (apoAI), inhibit
all three steps in the formation of MM-LDL. Pretreatment of LDL with
apoAI renders LDL resistant to oxidation and reduces the chemotactic
activity of LDL. ApoAI also renders LDL resistant to in vivo oxidation.
It removes 13(S)-hydroxyperoxyoctadecadienoic acid
[(13(S)-HPODE] and 15(S)-hydroxyperoxyeicosatetraenoic acid
[(15(S)-HPETE] from LDL. [(13(S)-HPODE] and [(15(S)-HPETE]
enhance the nonenzymatic oxidation of both
1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine and
cholesterol linoleate (108
, 109)
. This results in the
formation of three biologically active oxidized phospholipids: POVPC,
PGPC, and PEIPC.
Paraoxonase, a HDL-associated enzyme, prevents LDL oxidation by
hydrolyzing lipid peroxides, cholesterol linoleate hydroperoxides, and
hydrogen peroxide (110
111
112)
. Paraoxonase also renders HDL
resistant to oxidation, thereby maintaining the capacity of HDL to
induce reverse cholesterol transport. MM-LDL inhibits paraoxonase
expression (113)
. When fed a fat-rich diet, C57BL/6 mice
susceptible to atherosclerosis display decreased levels of paraoxonase
mRNA. However, mice resistant to atherosclerosis (C3H/HeJ) display a
decrease in hepatic paraoxonase mRNA levels (114)
. Shih
and collaborators (115)
recently demonstrated that
paraoxonase/apoE double knockout mice exhibit increased lipoprotein
oxidation and atherosclerosis compared with apoE knockout mice.
Recent investigations suggest that another HDL-associated enzyme
lecithin:cholesterol acyltransferase (LCAT) also prevents the
accumulation of oxidized lipids in LDL (116)
. Once MM-LDL
is present, it inhibits plasma LCAT activity and thereby impairs HDL
metabolism and reverse cholesterol transport (117
, 118)
.
The early inflammatory phase of atherosclerosis (119)
involves the generation of PAF and oxidized phospholipids with PAF-like
bioactivity in LDL (67)
. PAF is a potent lipid mediator
that stimulates macrophages to produce superoxide anions, thus
contributing to progression of atherosclerosis (120
, 121)
.
PAF and PAF-like oxidized phospholipids are inactivated by
PAF-acetylhydrolase (PAF-AH), a Ca2+-independent
enzyme that hydrolyzes the sn-2 group of PAF, converting it
into lyso-PAF (122)
. PAF-AH is released by monocytes and
macrophages, platelets, erythrocytes, spleen and liver cells
(123)
, and has anti-inflammatory properties
(124)
. Human PAF-AH is mainly associated with both LDL and
HDL (125)
. In mice, PAF-AH is predominantly associated
with HDL (126)
.
Transgenic apoE knockout overexpressing apoAI mice display
increased plasma PAF-AH activity and reduced oxidative stress
(127)
. Human-like HDL, generated by adenovirus-mediated
apoAI gene transfer, protects apoE knockout mice against neointima
formation (128)
.
Adenovirus-mediated gene transfer of PAF-AH in apoE knockout mice
results in a decrease in oxidative stress, deposition of oxidized LDL,
and accumulation of smooth muscle cells and macrophages in the arterial
wall. This finally results in reduction of injury-induced neointima
formation and prevention of spontaneous atherosclerosis, suggesting a
direct anti-atherogenic effect of PAF-AH (127
, 129)
. These
protective effects of HDL are summarized in Fig. 3
.
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Figure 3. Effect of HDL and HDL-associated enzymes on LDL oxidation. ApoAI
inhibits all three steps in the formation of MM-LDL. Paraoxonase
prevents LDL oxidation by hydrolyzing lipid peroxides, cholesterol
linoleate hydroperoxides, and hydrogen peroxide. MM-LDL inhibits
paraoxonase expression. LCAT prevents accumulation of oxidized lipids
in LDL. MM-LDL inhibits plasma LCAT activity and thereby impairs HDL
metabolism and reverse cholesterol transport. PAF and oxidized
phospholipids with PAF-like bioactivity in LDL stimulate macrophages to
produce superoxide anions, and thus stimulate the generation of MM-LDL
and OxLDL. PAF-AH is released by monocytes, macrophages, platelets,
erythrocytes, spleen and liver cells, and hydrolyzes the
sn-2 group of PAF, converting it to lyso-PAF. Plasma
PLTP promotes the net mass transfer of -tocopherol from HDL to
endothelial cells. Vitamin E prevents the endothelial dysfunction at an
early stage of atherosclerosis. HDL has a direct inhibitory effect on
the oxidized LDL-induced overexpression of ICAM-1 and VCAM-1 at the
surface of endothelial cells. Cholesterol delivered to macrophages by
oxidized LDL is primarily sequestered in lysosomes and thereby inhibits
normal cholesterol efflux.
|
|
Protective effect of HDL on endothelial function
Low HDL-C concentrations relate to lipoprotein oxidation and
endothelial dysfunction (130)
. -Tocopherol, the most
potent antioxidant form of vitamin E, is bound mainly to lipoproteins
in plasma; its incorporation into the vascular wall prevents the
endothelial dysfunction at an early stage of atherosclerosis
(131)
. The plasma phospholipid transfer protein (PLTP)
promotes the net mass transfer of -tocopherol from HDL to
endothelial cells. This transfer has two beneficial roles in preventing
endothelium damage: the antioxidant protection of membrane-bound
phospholipids and the preservation of the normal relaxing function of
vascular endothelial cells (Fig. 3)
.
Preservation of the relaxing function can be explained by
preservation of NO production. Oxidized LDL depletes caveolae of
cholesterol, resulting in the displacement of endothelial NOS (eNOS)
from caveolae and impaired eNOS activation (132)
.
CD36-blocking antibodies prevented oxidized LDL-induced redistribution
of eNOS, indicating that oxidized LDL–scavenger receptor interaction
is required. HDL binding to its specific receptor, scavenger receptor
class BI maintained the concentration of caveolae-associated
cholesterol by promoting the uptake of cholesterol esters,
thereby preventing oxidized LDL-induced depletion of caveola
cholesterol (Fig. 3)
.
HDL has a direct inhibitory effect on the oxidized LDL-induced
overexpression of both ICAM-1 and VCAM-1 at the surface of endothelial
cells (127
, 133
, 134
; Fig. 3
).
Effect of oxidized LDL on reverse cholesterol transport
The role of HDL in reverse cholesterol transport has been
emphasized during the past decade. However, in vitro experiments as
well as genetic family and population studies and investigations of
transgenic animals have revealed that HDL cholesterol levels do not
necessarily reflect the efficacy and the anti-atherogenicity of the
reverse cholesterol transport. Important determinants of HDL metabolism
and reverse cholesterol transport are the HDL-associated enzymes LCAT
and paraoxonase, which are inactivated by mild and extensive oxidized
LDL, resulting in an impairment of reverse cholesterol transport. It
has been demonstrated that cholesterol delivered to macrophages by
oxidized LDL is primarily sequestered in lysosomes and fails to efflux
normally (135)
. Thus, prevention of oxidation of LDL by
HDL is also beneficial for the active role of HDL in reverse
cholesterol transport and the regression of atherosclerotic
plaques.
|
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ABSTRACT
INTRODUCTION
