(Circulation. 1995;91:2488-2496.)
© 1995 American Heart Association, Inc.
Articles |
Atherosclerosis: Basic Mechanisms
Oxidation, Inflammation, and Genetics
From the Atherosclerosis Research Unit and the Departments of Medicine (J.A.B., M.N., A.M.F., J.S.F., L.L.D., P.A.E., A.J.L.), Pathology (J.A.B., A.D.W.), Physiology (J.S.F., L.L.D.), Biological Chemistry (P.A.E.), and Microbiology and Molecular Genetics (A.J.L.), University of California School of Medicine, Los Angeles, and the College of Letters and Sciences (A.J.L.), Los Angeles, Calif.
Correspondence to Alan M. Fogelman, MD, Department of Medicine, UCLA School of Medicine, Los Angeles, CA 90024-1736.
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Abstract |
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 Top Abstract IntroductionLipids and Atherogenesis Lipoprotein Retention in the...Lipoprotein Oxidation Mildly and Highly Oxidized...Oxidized LDL Is a...HDL May Protect by...Oxidation and Lesion Progression...Genetic Factors Affecting Lipid...Calcification and Plaque Rupture...Thrombosis Oxidation of LDL Produces...Pharmacological Intervention at...References |
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Abstract The clinical events resulting from atherosclerosis are directly related to the oxidation of lipids in LDLs that become trapped in the extracellular matrix of the subendothelial space. These oxidized lipids activate an NF
B-like transcription factor and induce
the expression of genes containing NFB binding sites. The protein
products of these genes initiate an inflammatory response that
initially leads to the development of the fatty streak. The progression
of the lesion is associated with the activation of genes that induce
arterial calcification, which changes the mechanical characteristics of
the artery wall and predisposes to plaque rupture at sites of monocytic
infiltration. Plaque rupture exposes the flowing blood to tissue factor
in the lesion, and this induces thrombosis, which is the proximate
cause of the clinical event. There appear to be potent genetically
determined systems for preventing lipid oxidation, inactivating
biologically important oxidized lipids, and/or modulating the
inflammatory response to oxidized lipids that may explain the differing
susceptibility of individuals and populations to the development of
atherosclerosis. Enzymes associated with HDL may play an important role
in protecting against lipid oxidation in the artery wall and may
account in part for the inverse relation between HDL and risk
for atherosclerotic clinical events.
Key Words: atherosclerosis • lipids • genes • antioxidants • lipoproteins
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Introduction |
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TopAbstractIntroductionLipids and Atherogenesis Lipoprotein Retention in the...Lipoprotein Oxidation Mildly and Highly Oxidized...Oxidized LDL Is a...HDL May Protect by...Oxidation and Lesion Progression...Genetic Factors Affecting Lipid...Calcification and Plaque Rupture...Thrombosis Oxidation of LDL Produces...Pharmacological Intervention at...References |
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At one time, atherosclerosis was thought to be a degenerative disease that was an inevitable consequence of aging. Research in the last two decades has shown that atherosclerosis is neither a degenerative disease nor inevitable. On the contrary, atherosclerosis seems to be a chronic inflammatory condition that is converted to an acute clinical event by the induction of plaque rupture, which in turn leads to thrombosis.1 What are the basic mechanisms that induce this sequence of events? Fig 1
depicts a model of the sequence of changes in the
artery wall that lead to a clinical event. The underlying hypothesis
presented here is that components of the earliest lesion, the fatty
streak, which itself is not clinically significant, are also
responsible for the latter events that lead to clinically significant
disease
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Lipids and Atherogenesis |
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TopAbstractIntroductionLipids and Atherogenesis Lipoprotein Retention in the...Lipoprotein Oxidation Mildly and Highly Oxidized...Oxidized LDL Is a...HDL May Protect by...Oxidation and Lesion Progression...Genetic Factors Affecting Lipid...Calcification and Plaque Rupture...Thrombosis Oxidation of LDL Produces...Pharmacological Intervention at...References |
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Table 1
depicts some of the steps in fatty
streak development. The first is lipoprotein transport into the artery
wall. This concentration-dependent process does not require
receptor-mediated endocytosis.2 3 The seminal
findings by
Brown and Goldstein4 that atherosclerosis is induced in
multiple species by mutations that involve a single gene, the LDL
receptor, provide strong evidence that elevations in LDL levels are
sufficient to induce all the components of the atherosclerotic
reaction.
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Lipoprotein Retention in the Artery Wall |
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TopAbstractIntroductionLipids and Atherogenesis Lipoprotein Retention in the...Lipoprotein Oxidation Mildly and Highly Oxidized...Oxidized LDL Is a...HDL May Protect by...Oxidation and Lesion Progression...Genetic Factors Affecting Lipid...Calcification and Plaque Rupture...Thrombosis Oxidation of LDL Produces...Pharmacological Intervention at...References |
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Schwenke and her late colleague Carew5 6 provided convincing evidence that for any given lipoprotein concentration in the plasma, lipoprotein retention in the artery wall was more important than the rate of transport into the artery wall. Kruth7 and Simionescu et al8 first reported early changes in the lipoproteins retained in the artery wall. Frank and Fogelman9 extended these findings with state-of-the-art ultrastructural techniques and demonstrated that LDL was rapidly transported across an intact endothelium and became trapped in the three-dimensional cage work of fibers and fibrils secreted by the artery wall cells.10 The intimate association of LDL11 with the extracellular matrix of the subendothelial space explains how the concentration of apolipoprotein B (apoB), the major protein of LDL, is found in higher concentrations in the artery wall than in the plasma.12 13 14 Early lesions appear to develop at sites of predilection15 16 17 18 19 20 21 22 that are related to hemodynamic and mechanical factors.23 24 25
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Lipoprotein Oxidation |
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TopAbstractIntroductionLipids and Atherogenesis Lipoprotein Retention in the...Lipoprotein Oxidation Mildly and Highly Oxidized...Oxidized LDL Is a...HDL May Protect by...Oxidation and Lesion Progression...Genetic Factors Affecting Lipid...Calcification and Plaque Rupture...Thrombosis Oxidation of LDL Produces...Pharmacological Intervention at...References |
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The cells of the artery wall secrete oxidative products from multiple pathways that can seed the LDL trapped in the subendothelial space and initiate lipid oxidation.26 27 28 29 Studies by Navab and colleagues30 with serum containing cocultures of human artery wall cells in which an endothelial monolayer was maintained on multilayers of smooth muscle cells indicated that the matrix provided by these artery wall cells could produce microenvironments that could exclude the water-soluble antioxidants of plasma. It is not surprising then that oxidative modification of the trapped lipoproteins does, in fact, occur, as was suggested more than a decade ago31 32 33 34 35 and subsequently proved in the late 1980s.36 37 38 39
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Mildly and Highly Oxidized LDL |
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TopAbstractIntroductionLipids and Atherogenesis Lipoprotein Retention in the...Lipoprotein Oxidation Mildly and Highly Oxidized...Oxidized LDL Is a...HDL May Protect by...Oxidation and Lesion Progression...Genetic Factors Affecting Lipid...Calcification and Plaque Rupture...Thrombosis Oxidation of LDL Produces...Pharmacological Intervention at...References |
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The oxidative modification of the trapped LDL is thought to occur in two stages. The first stage occurs before monocytes are recruited and results in the oxidization of lipids in LDL with little change in apoB. The second stage begins when monocytes are recruited to the lesion, convert into macrophages, and contribute their enormous oxidative capacity. In this second stage, the LDL lipids are further oxidized, but the protein portion of LDL is also modified, leading to a loss of recognition by the LDL receptor and a shift to recognition by the scavenger receptors and/or the oxidized LDL receptor.40 41 42 This shift in receptor recognition leads to cellular uptake of the LDL by receptors that are not regulated by the cholesterol content of the cell. The result is a massive accumulation of cholesterol. Such cholesterol-loaded cells have a foamy cytoplasm and have been called foam cells; they are the hallmark of the arterial fatty streak.
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Oxidized LDL Is a Potent Inducer of Inflammatory Molecules |
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TopAbstractIntroductionLipids and Atherogenesis Lipoprotein Retention in the...Lipoprotein Oxidation Mildly and Highly Oxidized...Oxidized LDL Is a...HDL May Protect by...Oxidation and Lesion Progression...Genetic Factors Affecting Lipid...Calcification and Plaque Rupture...Thrombosis Oxidation of LDL Produces...Pharmacological Intervention at...References |
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What are the mechanisms by which the oxidation of LDL leads to this inflammatory reaction? Berliner and colleagues43 reported that the mild oxidation of LDL yielded oxidized lipids that induced monocytes but not neutrophils to bind to endothelial cells. Treatment of endothelial cells with this oxidized lipid induced changes in molecules that affect all three stages44 of monocyte binding: tethering, activation, and attachment (Table 2
).
Levels of the tethering molecule P-selectin are
increased intracellularly by mildly oxidized LDL and can be released by
a variety of substances, including highly oxidized LDL.45
In vivo studies have also suggested that P-selectin can be released by
oxidized LDL,46 and P-selectin expression has been shown
to be increased in human lesions.45 47 Moreover,
mildly
oxidized LDL induced endothelial cells to produce the potent monocyte
activators monocyte chemoattractant protein 1 (MCP-1),48
monocyte colony stimulating factor (M-CSF),49 and
GRO.50 While M-CSF and MCP-1 appear to be soluble
molecules, GRO was found bound to heparin-like molecules on the
endothelial cell surface.50 Another adhesion molecule,
VCAM-1, has been implicated in the development of fatty streaks in
rabbits.51 Mildly oxidized LDL does not induce VCAM-1 or
ICAM-1 expression,52 and the adhesion molecule induced by
mildly oxidized LDL has yet to be completely identified. Navab and
colleagues30 demonstrated that LDL added to cocultures of
human aortic endothelial and smooth muscle cells also led to the
production of MCP-1 and monocyte migration into the subendothelial
space. Rajavashisth and colleagues49 demonstrated the
presence of M-CSF in atherosclerotic lesions in rabbits. Subsequent to
these findings, others reported that MCP-1 and M-CSF were present
in lesions from animals and humans.53 54 Studies by
Cushing and Fogelman55 suggested that differentiating
monocytes also produced MCP-1 that could amplify their own recruitment
into lesions. Consistent with this hypothesis was the finding by Neiken
and colleagues56 that MCP-1 was expressed most in lesion
areas where monocyte density was greatest. Charo and
colleagues57 recently cloned the receptor for MCP-1,
providing a potential new target for interrupting this reaction.
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How does mildly oxidized LDL induce a set of genes with protein products that lead to monocyte adherence, migration, and conversion into macrophages without inducing a neutrophilic or lymphocytic reaction? Parhami and colleagues58 reported that mildly oxidized LDL induces elevated levels of cAMP by a G protein–mediated mechanism. These high levels of cAMP decrease the expression of ELAM-1 (a receptor to which neutrophils bind) while increasing the molecules noted above. Mildly oxidized LDL induces these inflammatory molecules both by inducing increased rates of gene transcription and by stabilizing the mRNA for these genes.59
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HDL May Protect by Inhibiting LDL Oxidation |
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TopAbstractIntroductionLipids and Atherogenesis Lipoprotein Retention in the...Lipoprotein Oxidation Mildly and Highly Oxidized...Oxidized LDL Is a...HDL May Protect by...Oxidation and Lesion Progression...Genetic Factors Affecting Lipid...Calcification and Plaque Rupture...Thrombosis Oxidation of LDL Produces...Pharmacological Intervention at...References |
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HDL was found to protect against LDL oxidation by metal ions in vitro60 61 and to prevent the production of mildly oxidized LDL by the artery wall cells in a coculture model.30 However, HDL obtained either from patients undergoing surgery or after myocardial infarction in which apolipoprotein A-I was displaced from the HDL by the acute phase reactant serum amyloid A not only was not protective against LDL modification but actually enhanced LDL modification by the cocultures.62 Two enzyme systems associated with normal HDL have been reported to inhibit LDL oxidation in vitro. Stafforini and colleagues63 reported that the platelet activating factor acetylhydrolase was effective in preventing metal ion–dependent oxidation of LDL. Mackness and colleagues64 reported that a second enzyme associated with HDL, paraoxonase, also inhibited LDL oxidation in vitro. Both enzymes have been found to protect against LDL modification in the coculture system.65 66 Thus, the inverse relation between risk for atherosclerotic events and HDL levels may be due to enzymes associated with HDL that protect against LDL oxidation and the putative role of HDL in reverse cholesterol transport.67 Moreover, because these enzymes are associated with only a small fraction of HDL particles, this may, in part, explain why some patients with low levels of total HDL cholesterol may not have clinically significant atherosclerosis and others with relatively normal levels of HDL cholesterol may have premature atherosclerosis. However, this hypothesis has yet to be tested.
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Oxidation and Lesion Progression |
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TopAbstractIntroductionLipids and Atherogenesis Lipoprotein Retention in the...Lipoprotein Oxidation Mildly and Highly Oxidized...Oxidized LDL Is a...HDL May Protect by...Oxidation and Lesion Progression...Genetic Factors Affecting Lipid...Calcification and Plaque Rupture...Thrombosis Oxidation of LDL Produces...Pharmacological Intervention at...References |
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Fig 2
depicts in cartoon form some
of the molecular and cellular mechanisms responsible for the sequence
of events described in Fig 1
. This scheme would predict that
conditions
that increased the oxidative waste of artery wall cells would increase
the seeding of LDL trapped in the subendothelial space, as suggested by
Witztum and Steinberg26 29 and
Parthasarathy.27 28 Increased levels of HDL
containing
enzymes that prevented the formation of or destroyed the biologically
active lipids generated in the mildly oxidized LDL would prevent the
ensuing inflammatory reaction. Once started, however, the reaction
would tend to amplify itself. Navab et al68 reported that
artery wall cells interacted with monocytes by inducing mRNA for the
gap junction protein connexin43, which was accompanied by increased
production of matrix molecules and involved interleukin-1 (IL-1) and
interleukin-6. Ross69 demonstrated that monocyte
macrophages are a potent source of a powerful smooth muscle cell growth
factor and chemoattractant platelet-derived growth factor (PDGF). This
would explain, in part, the migration of smooth muscle cells into the
lesion. Products of lipoprotein oxidation have also been shown to
affect other events associated with atherogenesis. The secretion of
IL-1, a growth factor for smooth muscle cells, has been shown to be
stimulated by oxidized lipids.70 Lysophosphatidylcholine,
a product of LDL oxidation, has been shown to be a chemoattractant for
monocytes71 and T-lymphocytes,72 to induce
the adhesion molecules VCAM-1 and ICAM-1,73 and to
increase levels of PDGF and heparin-binding epidermal growth factor
mRNA in endothelial cells74 and smooth muscle
cells.75 Highly oxidized LDL also can inhibit endothelial
cell migration and may impair the repair of ulcerated plaques in
advanced lesions.76 Highly oxidized LDL has also been
shown to be toxic to macrophages77 and as a result may
contribute to amplification of the inflammatory process and the
formation of the necrotic core found in advanced lesions. With the
death of some of the macrophage foam cells, lipid droplets could be
released and phagocytized by the smooth muscle cells, producing smooth
muscle cell foam cells, as suggested by Wolfbauer and
colleagues.78 The involvement of the immune system in the
development of lesions79 80 81 may
increase82 or
decrease83 84 the inflammatory reaction.
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Glagov et al85 demonstrated that in all species the lesion grows out toward the adventitia until a critical point is reached, at which time the lesion can no longer expand outward at the expense of the normal media and then begins to encroach on the lumen. The lesion grows by the migration of new mononuclear cells that enter at the shoulder regions of the lesion,86 the proliferation of both monocyte macrophages87 and smooth muscle cells,88 the production of an exuberant extracellular matrix,89 and the accumulation of extracellular lipid in a necrotic core.7 90
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Genetic Factors Affecting Lipid Oxidation and Inflammation |
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TopAbstractIntroductionLipids and Atherogenesis Lipoprotein Retention in the...Lipoprotein Oxidation Mildly and Highly Oxidized...Oxidized LDL Is a...HDL May Protect by...Oxidation and Lesion Progression...Genetic Factors Affecting Lipid...Calcification and Plaque Rupture...Thrombosis Oxidation of LDL Produces...Pharmacological Intervention at...References |
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Liao and colleagues91 reasoned that if oxidized lipids were responsible for the induction of a set of genes that induced the chronic inflammatory response characteristic of the fatty streak, these genes might be induced in any tissue that accumulated the oxidized lipids. They used mouse livers as a convenient tissue for detailed genetic studies. Mice that readily develop fatty streaks in their aortas on an atherogenic diet (C57BL/6) were compared with mice that never developed fatty streaks on the same atherogenic diet (C3H/HeJ), despite the fact that the two strains develop similar levels of the atherogenic apoB-containing lipoproteins in their blood on this diet. On the atherogenic diet, both strains accumulated substantial amounts of total lipid, cholesterol, and triglycerides in their livers that did not significantly differ between the two strains. However, the fatty streak–susceptible strain (C57BL/6) accumulated significantly more oxidized lipid than did the fatty streak–resistant strain (C3H/HeJ). Associated with these higher levels of oxidized lipids was the activation of an NF
B-like transcription factor and the
expression of genes that contain NFB binding sites: JE,
the mouse homologue of MCP-1, colony stimulating factors, serum amyloid
A, and heme oxygenase in the fatty streak–susceptible C57BL/6 mice but
not in the fatty streak–resistant C3H/HeJ
mice.91 92
Injection of mildly oxidized LDL into the mice induced the same set of
genes in the liver.91 93 These results were
consistent
with the hypothesis that the atherogenic diet resulted in the
accumulation of oxidized lipids in certain tissues (eg, liver and
arteries), with the resulting inflammatory response to this oxidative
stress genetically determined.94 While these data were
suggestive of a genetically determined rate of formation or destruction
of oxidized lipids or that the intensity of the inflammatory response
to these lipids was genetically determined, the association or lack of
association of these phenomena with two genetically distinct strains
did not directly prove a genetic link. Fortunately, recombinant inbred
strains derived from the parental strains were available to directly
test the hypothesis. Crossbreeding of the parental strains allowed the
genomes of the two strains to be extensively intermingled because of
chromosomal crossover. If the level of oxidized lipids, the activation
of the NFB-like transcription factor, the expression of the
inflammatory genes, and the development of aortic fatty streaks all
cosegregated together as the two genomes were randomly distributed by
extensive crossbreeding, it would be strong evidence that these
phenomena were genetically linked. Results of the analysis revealed
that indeed there was cosegregation and suggested that a major gene
contributing to aortic lesion development in this mouse model,
previously termed Ath-1, may control either the accumulation
of lipid peroxides in tissues or the cellular responses to such lipid
peroxides.95 |
Calcification and Plaque Rupture |
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TopAbstractIntroductionLipids and Atherogenesis Lipoprotein Retention in the...Lipoprotein Oxidation Mildly and Highly Oxidized...Oxidized LDL Is a...HDL May Protect by...Oxidation and Lesion Progression...Genetic Factors Affecting Lipid...Calcification and Plaque Rupture...Thrombosis Oxidation of LDL Produces...Pharmacological Intervention at...References |
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Recent evidence suggests that the site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques is characterized by an inflammatory process regardless of the dominant plaque morphology.96 97 It is thought that mechanical factors are involved in the actual rupture of the plaque at such sites of structural weakness. Demer98 reported that the mechanical characteristics of atherosclerotic plaque are due to calcification of the lesions. Fig 3
demonstrates that the mechanical
characteristics observed in human coronary arteries were not reproduced
in the aorta of rabbits with LDL receptor deficiency even when they
were placed on a cholesterol-rich diet and had extensive aortic
atherosclerosis. However, as Fig 3 shows, when the aortas of
these
animals were induced to calcify, they had mechanical characteristics
identical to those seen in atherosclerotic human coronary arteries.
Demer et al99 argued that the presence of a soft plaque
with a point of weakness induced by inflammation sitting on an area of
calcification predisposes to plaque rupture because of the presence of
a tissue interface of differing physical properties that is subjected
to the pulsatile changes of the arterial blood pressure. "Hardening
of the arteries" has long been thought to be an inevitable
consequence of aging. However, Demer and her colleagues99
reported that this is no more an inevitable degenerative change than is
the development of other components of the inflammatory reaction.
Bostrom et al100 and Watson et al101
demonstrated that a heretofore unrecognized cell in large and medium
arteries is responsible for calcification. This cell has many of the
characteristics of pericytes found in the microcirculation. These
cells, called calcifying vascular cells, were induced to calcify by
expression of the same set of genes as those expressed during bone
formation. The expression of these genes was induced by tissue growth
factor-ß and oxysterol, two agents known to be present in the
fatty streak and the developing atherosclerotic lesion. It is possible
that other chronic inflammatory reactions such as tuberculosis may
induce calcification by similar mechanisms. In the artery wall,
however, the calcification-induced changes in the mechanical
characteristics of the tissue predispose to plaque
rupture.102 103 104 105 106
Recent studies in mice indicate that
arterial calcification may be under genetic control.107
The changes in the mechanical characteristics of the arterial tissue
induced by calcification are superimposed on changes in the matrix that
result from increased expression of matrix metalloproteinases and
matrix degrading activity in the shoulder region of the
lesion.108 109 Thus, mechanical forces are applied to
an
area of structural weakness and predispose to plaque rupture.
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Thrombosis |
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TopAbstractIntroductionLipids and Atherogenesis Lipoprotein Retention in the...Lipoprotein Oxidation Mildly and Highly Oxidized...Oxidized LDL Is a...HDL May Protect by...Oxidation and Lesion Progression...Genetic Factors Affecting Lipid...Calcification and Plaque Rupture...Thrombosis Oxidation of LDL Produces...Pharmacological Intervention at...References |
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The endothelium usually has anticoagulant properties. The potent coagulant, tissue factor, usually is expressed only in the adventitia. (This makes teleological sense because one would want to induce clotting if the artery were opened to the adventitial side.) Oxidized LDL has been shown to induce endothelial cells110 111 and monocytes112 to express high levels of tissue factor. In addition, Drake and colleagues113 demonstrated that there is abundant tissue factor in the intima of atherosclerotic lesions. Plasminogen activator inhibitor levels are also increased when endothelial cells are exposed to oxidized LDL.114 Consequently, plaque rupture would expose the flowing blood to these high levels of tissue factor and result in clotting with the induction of a clinical event. The normal response to thrombin formation is vasodilation,115 which would favor the mechanical removal of a clot. Oxidized LDL has been shown to induce the expression of endothelin,116 to inhibit the expression of nitric oxide synthase, and to inhibit the resulting vasodilation.117 118 119 Thus, LDL further contributes to arterial occlusion by thrombus. In addition to the local reduction in nitric oxide, it is also quite clear that platelet accumulation and local increases in thromboxane A2, serotonin, ADP, platelet activating factor, and activated thrombin, together with a local reduction in prostacyclin, contribute to thrombosis.120 121
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Oxidation of LDL Produces Oxidized Lipids With Differing Biological Activities |
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TopAbstractIntroductionLipids and Atherogenesis Lipoprotein Retention in the...Lipoprotein Oxidation Mildly and Highly Oxidized...Oxidized LDL Is a...HDL May Protect by...Oxidation and Lesion Progression...Genetic Factors Affecting Lipid...Calcification and Plaque Rupture...Thrombosis Oxidation of LDL Produces...Pharmacological Intervention at...References |
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Atherosclerotic lesions contain multiple oxidized lipids derived from the lipids in LDL.122 The biological properties of the lipids in mildly oxidized LDL have been seen to be different from those induced by the lipids in highly oxidized LDL (eg, the expression of tissue factor by endothelial cells was induced by mildly oxidized LDL but not by highly oxidized LDL110 ; the lipids in highly oxidized LDL were cytotoxic,123 whereas the lipids in mildly oxidized LDL were not43 ). Fig 4
depicts a scheme in which LDL undergoes various degrees of oxidation.
The activation of the NFB-like transcription factor and the increase
in the genes induced by mildly oxidized LDL are due to the appearance
of specific oxidized lipids that appear to be oxidized phospholipids
but are as yet unidentified.65 66 With continued
oxidation, these bioactive lipids are presumed to be destroyed and new
ones formed that account for the different biological activity of
highly oxidized LDL. These latter lipids include
lysophosphatidylcholine and oxidized
sterols.71 73 74 75 123
The final identification of the specific biologically active lipids in
mildly oxidized LDL will likely yield new targets of opportunity for
intervention. One possibility is that these lipids are by chance
similar to lipids in bacteria that evoke similar chronic inflammatory
responses such as Mycobacterium
tuberculosis.124
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Pharmacological Intervention at the Level of the Artery Wall |
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TopAbstractIntroductionLipids and Atherogenesis Lipoprotein Retention in the...Lipoprotein Oxidation Mildly and Highly Oxidized...Oxidized LDL Is a...HDL May Protect by...Oxidation and Lesion Progression...Genetic Factors Affecting Lipid...Calcification and Plaque Rupture...Thrombosis Oxidation of LDL Produces...Pharmacological Intervention at...References |
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The prevention and treatment of atherosclerosis currently are appropriately directed to lowering LDL levels and raising HDL levels. As we understand the basic mechanisms more fully, new strategies may emerge.125 We may learn how to specifically raise the levels of HDL subfractions that carry the enzymes that prevent the formation of or destroy the biologically active lipids in oxidized LDL. If we can identify the major genes that control the formation of biologically active oxidized lipids or control the intensity of the response to these lipids, we may be able to devise strategies that will favorably modify the functions controlled by these genes. As we understand the basic mechanisms of arterial calcification, we may be able to devise strategies that will allow us to maintain normal artery wall mechanics and prevent plaque rupture. So far, at least one anti-inflammatory compound has been identified that inhibits in vitro the formation of biologically active mildly oxidized LDL and smooth muscle proliferation without inhibiting endothelial cell proliferation.126 127 The future will undoubtedly reveal a number of new strategies for preventing and treating atherosclerosis.
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Acknowledgments |
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This work was supported in part by NIH grant HL-30568 and the M.K. Grey and Laubisch Funds at the University of California, Los Angeles.
Received January 9, 1995; revision received February 27, 1995; accepted February 28, 1995.
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References |
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TopAbstractIntroductionLipids and Atherogenesis Lipoprotein Retention in the...Lipoprotein Oxidation Mildly and Highly Oxidized...Oxidized LDL Is a...HDL May Protect by...Oxidation and Lesion Progression...Genetic Factors Affecting Lipid...Calcification and Plaque Rupture...Thrombosis Oxidation of LDL Produces...Pharmacological Intervention at...References |
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D. T. Bolick, A. M. Whetzel, M. Skaflen, T. L. Deem, J. Lee, and C. C. Hedrick Absence of the G Protein-Coupled Receptor G2A in Mice Promotes Monocyte/Endothelial Interactions in Aorta Circ. Res., March 2, 2007; 100(4): 572 - 580. [Abstract] [Full Text] [PDF]
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S. M. Colgan and R. C. Austin Homocysteinylation of Metallothionein Impairs Intracellular Redox Homeostasis: The Enemy Within! Arterioscler Thromb Vasc Biol, January 1, 2007; 27(1): 8 - 11. [Full Text] [PDF]
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M. Ditiatkovski, B.-H. Toh, and A. Bobik GM-CSF Deficiency Reduces Macrophage PPAR-{gamma} Expression and Aggravates Atherosclerosis in ApoE-Deficient Mice Arterioscler Thromb Vasc Biol, October 1, 2006; 26(10): 2337 - 2344. [Abstract] [Full Text] [PDF]
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A. Guven, A. Cetinkaya, M. Aral, G. Sokmen, M. A. Buyukbese, A. Guven, and N. Koksal High-Sensitivity C-Reactive Protein in Patients with Metabolic Syndrome Angiology, May 1, 2006; 57(3): 295 - 302. [Abstract] [PDF]
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A. D. Mooradian, M. J. Haas, and N. C. W. Wong The Effect of Select Nutrients on Serum High-Density Lipoprotein Cholesterol and Apolipoprotein A-I Levels Endocr. Rev., February 1, 2006; 27(1): 2 - 16. [Abstract] [Full Text] [PDF]
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A. Gutierrez, E. P. Ratliff, A. M. Andres, X. Huang, W. L. McKeehan, and R. A. Davis Bile Acids Decrease Hepatic Paraoxonase 1 Expression and Plasma High-Density Lipoprotein Levels Via FXR-Mediated Signaling of FGFR4 Arterioscler Thromb Vasc Biol, February 1, 2006; 26(2): 301 - 306. [Abstract] [Full Text] [PDF]
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 J. Cai, T. S. Hatsukami, M. S. Ferguson, W. S. Kerwin, T. Saam, B. Chu, N. Takaya, N. L. Polissar, and C. Yuan In Vivo Quantitative Measurement of Intact Fibrous Cap and Lipid-Rich Necrotic Core Size in Atherosclerotic Carotid Plaque: Comparison of High-Resolution, Contrast-Enhanced Magnetic Resonance Imaging and Histology Circulation, November 29, 2005; 112(22): 3437 - 3444. [Abstract] [Full Text] [PDF]
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M. Xia, M. Hou, H. Zhu, J. Ma, Z. Tang, Q. Wang, Y. Li, D. Chi, X. Yu, T. Zhao, et al. Anthocyanins Induce Cholesterol Efflux from Mouse Peritoneal Macrophages: THE ROLE OF THE PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR {gamma}-LIVER X RECEPTOR {alpha}-ABCA1 PATHWAY J. Biol. Chem., November 4, 2005; 280(44): 36792 - 36801. [Abstract] [Full Text] [PDF]
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C. De Ciuceis, F. Amiri, P. Brassard, D. H. Endemann, R. M. Touyz, and E. L. Schiffrin Reduced Vascular Remodeling, Endothelial Dysfunction, and Oxidative Stress in Resistance Arteries of Angiotensin II-Infused Macrophage Colony-Stimulating Factor-Deficient Mice: Evidence for a Role in Inflammation in Angiotensin-Induced Vascular Injury Arterioscler Thromb Vasc Biol, October 1, 2005; 25(10): 2106 - 2113. [Abstract] [Full Text] [PDF]
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N. Androulakis, H. Durand, E. Ninio, and D. C. Tsoukatos Molecular and mechanistic characterization of platelet-activating factor-like bioactivity produced upon LDL oxidation J. Lipid Res., September 1, 2005; 46(9): 1923 - 1932. [Abstract] [Full Text] [PDF]
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C. Meisinger, J. Baumert, N. Khuseyinova, H. Loewel, and W. Koenig Plasma Oxidized Low-Density Lipoprotein, a Strong Predictor for Acute Coronary Heart Disease Events in Apparently Healthy, Middle-Aged Men From the General Population Circulation, August 2, 2005; 112(5): 651 - 657. [Abstract] [Full Text] [PDF]
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D. T. Bolick, S. Srinivasan, K. W. Kim, M. E. Hatley, J. J. Clemens, A. Whetzel, N. Ferger, T. L. Macdonald, M. D. Davis, P. S. Tsao, et al. Sphingosine-1-Phosphate Prevents Tumor Necrosis Factor-{alpha}-Mediated Monocyte Adhesion to Aortic Endothelium in Mice Arterioscler Thromb Vasc Biol, May 1, 2005; 25(5): 976 - 981. [Abstract] [Full Text] [PDF]
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C. Giannattasio, A. Zoppo, G. Gentile, M. Failla, A. Capra, F.M. Maggi, A. Catapano, and G. Mancia Acute Effect of High-Fat Meal on Endothelial Function in Moderately Dyslipidemic Subjects Arterioscler Thromb Vasc Biol, February 1, 2005; 25(2): 406 - 410. [Abstract] [Full Text] [PDF]
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J. D. Morrow Quantification of Isoprostanes as Indices of Oxidant Stress and the Risk of Atherosclerosis in Humans Arterioscler Thromb Vasc Biol, February 1, 2005; 25(2): 279 - 286. [Abstract] [Full Text] [PDF]
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J. Viereck, F. L. Ruberg, Y. Qiao, A. S. Perez, K. Detwiller, M. Johnstone, and J. A. Hamilton MRI of Atherothrombosis Associated With Plaque Rupture Arterioscler Thromb Vasc Biol, January 1, 2005; 25(1): 240 - 245. [Abstract] [Full Text] [PDF]
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S. D. Nguyen and D.-E. Sok Preferential inhibition of paraoxonase activity of human paraoxonase 1 by negatively charged lipids J. Lipid Res., December 1, 2004; 45(12): 2211 - 2220. [Abstract] [Full Text] [PDF]
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S. Seibold, D. Schurle, A. Heinloth, G. Wolf, M. Wagner, and J. Galle Oxidized LDL Induces Proliferation and Hypertrophy in Human Umbilical Vein Endothelial Cells via Regulation of p27Kip1 Expression: Role of RhoA J. Am. Soc. Nephrol., December 1, 2004; 15(12): 3026 - 3034. [Abstract] [Full Text] [PDF]
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A. Kampschulte, M.S. Ferguson, W.S. Kerwin, N. L. Polissar, B. Chu, T. Saam, T.S. Hatsukami, and C. Yuan Differentiation of Intraplaque Versus Juxtaluminal Hemorrhage/Thrombus in Advanced Human Carotid Atherosclerotic Lesions by In Vivo Magnetic Resonance Imaging Circulation, November 16, 2004; 110(20): 3239 - 3244. [Abstract] [Full Text] [PDF]
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W. Shi, H. Pei, J. J. Fischer, J. C. James, J. F. Angle, A. H. Matsumoto, G. A. Helm, and I. J. Sarembock Neointimal formation in two apolipoprotein E-deficient mouse strains with different atherosclerosis susceptibility J. Lipid Res., November 1, 2004; 45(11): 2008 - 2014. [Abstract] [Full Text] [PDF]
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X. L. Wang, D. L Rainwater, M. C Mahaney, and R. Stocker Cosupplementation with vitamin E and coenzyme Q10 reduces circulating markers of inflammation in baboons Am. J. Clinical Nutrition, September 1, 2004; 80(3): 649 - 655. [Abstract] [Full Text] [PDF]
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S. T. Reddy, J. T. Nguyen, V. Grijalva, G. Hough, S. Hama, M. Navab, and A. M. Fogelman Potential Role for Mitogen-Activated Protein Kinase Phosphatase-1 in the Development of Atherosclerotic Lesions in Mouse Models Arterioscler Thromb Vasc Biol, September 1, 2004; 24(9): 1676 - 1681. [Abstract] [Full Text] [PDF]
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J. Golledge, M. McCann, S. Mangan, A. Lam, and M. Karan Osteoprotegerin and Osteopontin Are Expressed at High Concentrations Within Symptomatic Carotid Atherosclerosis Stroke, July 1, 2004; 35(7): 1636 - 1641. [Abstract] [Full Text] [PDF]
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S. Keidar, M. Kaplan, E. Pavlotzky, R. Coleman, T. Hayek, S. Hamoud, and M. Aviram Aldosterone Administration to Mice Stimulates Macrophage NADPH Oxidase and Increases Atherosclerosis Development: A Possible Role for Angiotensin-Converting Enzyme and the Receptors for Angiotensin II and Aldosterone Circulation, May 11, 2004; 109(18): 2213 - 2220. [Abstract] [Full Text] [PDF]
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E. Kanters, M. J.J. Gijbels, I. van der Made, M. N. Vergouwe, P. Heeringa, G. Kraal, M. H. Hofker, and M. P. J. de Winther Hematopoietic NF-{kappa}B1 deficiency results in small atherosclerotic lesions with an inflammatory phenotype Blood, February 1, 2004; 103(3): 934 - 940. [Abstract] [Full Text] [PDF]
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J. Hwang, M. H. Ing, A. Salazar, B. Lassegue, K. Griendling, M. Navab, A. Sevanian, and T. K. Hsiai Pulsatile Versus Oscillatory Shear Stress Regulates NADPH Oxidase Subunit Expression: Implication for Native LDL Oxidation Circ. Res., December 12, 2003; 93(12): 1225 - 1232. [Abstract] [Full Text] [PDF]
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S. Deakin, I. Leviev, S. Guernier, and R. W. James Simvastatin Modulates Expression of the PON1 Gene and Increases Serum Paraoxonase: A Role for Sterol Regulatory Element-Binding Protein-2 Arterioscler Thromb Vasc Biol, November 1, 2003; 23(11): 2083 - 2089. [Abstract] [Full Text] [PDF]
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R. P. Tracy Thrombin, Inflammation, and Cardiovascular Disease: An Epidemiologic Perspective Chest, September 1, 2003; 124 (2009): 49S - 57S. [Abstract] [Full Text] [PDF]
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J. Barkhausen, W. Ebert, C. Heyer, J. F. Debatin, and H.-J. Weinmann Detection of Atherosclerotic Plaque With Gadofluorine-Enhanced Magnetic Resonance Imaging Circulation, August 5, 2003; 108(5): 605 - 609. [Abstract] [Full Text] [PDF]
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D. M. Golodne, R. Q. Monteiro, A. V. Graca-Souza, M. A. C. Silva-Neto, and G. C. Atella Lysophosphatidylcholine Acts as an Anti-hemostatic Molecule in the Saliva of the Blood-sucking Bug Rhodnius prolixus J. Biol. Chem., July 18, 2003; 278(30): 27766 - 27771. [Abstract] [Full Text] [PDF]
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C.-y. Yang, J. L. Raya, H.-H. Chen, C.-H. Chen, Y. Abe, H. J. Pownall, A. A. Taylor, and C. V. Smith Isolation, Characterization, and Functional Assessment of Oxidatively Modified Subfractions of Circulating Low-Density Lipoproteins Arterioscler Thromb Vasc Biol, June 1, 2003; 23(6): 1083 - 1090. [Abstract] [Full Text] [PDF]
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M. Danner, S. V. Kasl, J. L. Abramson, and V. Vaccarino Association Between Depression and Elevated C-Reactive Protein Psychosom Med, May 1, 2003; 65(3): 347 - 356. [Abstract] [Full Text] [PDF]
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G. N. Fredrikson, B. Hedblad, G. Berglund, R. Alm, M. Ares, B. Cercek, K.-Y. Chyu, P. K. Shah, and J. Nilsson Identification of Immune Responses Against Aldehyde-Modified Peptide Sequences in ApoB Associated With Cardiovascular Disease Arterioscler Thromb Vasc Biol, May 1, 2003; 23(5): 872 - 878. [Abstract] [Full Text] [PDF]
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A. E. May, V. Redecke, S. Gruner, R. Schmidt, S. Massberg, T. Miethke, B. Ryba, C. Prazeres da Costa, A. Schomig, and F.-J. Neumann Recruitment of Chlamydia pneumoniae-Infected Macrophages to the Carotid Artery Wall in Noninfected, Nonatherosclerotic Mice Arterioscler Thromb Vasc Biol, May 1, 2003; 23(5): 789 - 794. [Abstract] [Full Text] [PDF]
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H. Kirii, T. Niwa, Y. Yamada, H. Wada, K. Saito, Y. Iwakura, M. Asano, H. Moriwaki, and M. Seishima Lack of Interleukin-1{beta} Decreases the Severity of Atherosclerosis in ApoE-Deficient Mice Arterioscler Thromb Vasc Biol, April 1, 2003; 23(4): 656 - 660. [Abstract] [Full Text] [PDF]
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M. Schoppet, A. M. Sattler, J. R. Schaefer, M. Herzum, B. Maisch, and L. C. Hofbauer Increased Osteoprotegerin Serum Levels in Men with Coronary Artery Disease J. Clin. Endocrinol. Metab., March 1, 2003; 88(3): 1024 - 1028. [Abstract] [Full Text] [PDF]
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J. D. Morrow Is Oxidant Stress a Connection Between Obesity and Atherosclerosis? Arterioscler Thromb Vasc Biol, March 1, 2003; 23(3): 368 - 370. [Full Text] [PDF]
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R. De Caterina and C. Manes Inflammation in early atherogenesis: impact of ACE inhibition Eur. Heart J. Suppl., January 1, 2003; 5(suppl_A): A15 - A24. [Abstract] [PDF]
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C. R. Kiefer, J. B. McKenney, J. F. Trainor, and L. M. Snyder Maturation-Dependent Acquired Coronary Structural Alterations and Atherogenesis in the Dahl Sodium-Sensitive Hypertensive Rat Circulation, November 5, 2002; 106(19): 2486 - 2490. [Abstract] [Full Text] [PDF]
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K. Nishi, H. Itabe, M. Uno, K. T. Kitazato, H. Horiguchi, K. Shinno, and S. Nagahiro Oxidized LDL in Carotid Plaques and Plasma Associates With Plaque Instability Arterioscler Thromb Vasc Biol, October 1, 2002; 22(10): 1649 - 1654. [Abstract] [Full Text] [PDF]
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H. Kaneda, M. Ohno, J. Taguchi, M. Togo, H. Hashimoto, K. Ogasawara, T. Aizawa, N. Ishizaka, and R. Nagai Heme Oxygenase-1 Gene Promoter Polymorphism Is Associated With Coronary Artery Disease in Japanese Patients With Coronary Risk Factors Arterioscler Thromb Vasc Biol, October 1, 2002; 22(10): 1680 - 1685. [Abstract] [Full Text] [PDF]
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V. Raos and B. J. Strujic Dyslipoproteinemia and Coronary Disease Angiology, September 1, 2002; 53(5): 557 - 562. [Abstract] [PDF]
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 I. Bureau, F. Laporte, M. Favier, H. Faure, M. Fields, A. E. Favier, and A.-M. Roussel No Antioxidant Effect of Combined HRT on LDL Oxidizability and Oxidative Stress Biomarkers in Treated Post-Menopausal Women J. Am. Coll. Nutr., August 1, 2002; 21(4): 333 - 338. [Abstract] [Full Text] [PDF]
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T. C. Major, L. Liang, X. Lu, W. Rosebury, and T. M.A. Bocan Extracellular Matrix Metalloproteinase Inducer (EMMPRIN) Is Induced Upon Monocyte Differentiation and Is Expressed in Human Atheroma Arterioscler Thromb Vasc Biol, July 1, 2002; 22(7): 1200 - 1207. [Abstract] [Full Text] [PDF]
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L. J. Pinderski, M. P. Fischbein, G. Subbanagounder, M. C. Fishbein, N. Kubo, H. Cheroutre, L. K. Curtiss, J. A. Berliner, and W. A. Boisvert Overexpression of Interleukin-10 by Activated T Lymphocytes Inhibits Atherosclerosis in LDL Receptor-Deficient Mice by Altering Lymphocyte and Macrophage Phenotypes Circ. Res., May 31, 2002; 90(10): 1064 - 1071. [Abstract] [Full Text] [PDF]
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J. L. Sanchez-Quesada, S. Benitez, C. Otal, M. Franco, F. Blanco-Vaca, and J. Ordonez-Llanos Density distribution of electronegative LDL in normolipemic and hyperlipemic subjects J. Lipid Res., May 1, 2002; 43(5): 699 - 705. [Abstract] [Full Text] [PDF]
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E. Boisfer, D. Stengel, D. Pastier, P. M. Laplaud, N. Dousset, E. Ninio, and A.-D. Kalopissis Antioxidant properties of HDL in transgenic mice overexpressing human apolipoprotein A-II J. Lipid Res., May 1, 2002; 43(5): 732 - 741. [Abstract] [Full Text] [PDF]
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 B. A. Wasserman, W. I. Smith, H. H. Trout III, R. O. Cannon III, R. S. Balaban, and A. E. Arai Carotid Artery Atherosclerosis: In Vivo Morphologic Characterization with Gadolinium-enhanced Double-oblique MR Imaging—Initial Results Radiology, May 1, 2002; 223(2): 566 - 573. [Abstract] [Full Text] [PDF]
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 T. E. Akiyama, S. Sakai, G. Lambert, C. J. Nicol, K. Matsusue, S. Pimprale, Y.-H. Lee, M. Ricote, C. K. Glass, H. B. Brewer Jr., et al. Conditional Disruption of the Peroxisome Proliferator-Activated Receptor {gamma} Gene in Mice Results in Lowered Expression of ABCA1, ABCG1, and apoE in Macrophages and Reduced Cholesterol Efflux Mol. Cell. Biol., April 15, 2002; 22(8): 2607 - 2619. [Abstract] [Full Text] [PDF]
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F. Basso, G. D.O. Lowe, A. Rumley, A. D. McMahon, and S. E. Humphries Interleukin-6 -174G>C Polymorphism and Risk of Coronary Heart Disease in West of Scotland Coronary Prevention Study (WOSCOPS) Arterioscler Thromb Vasc Biol, April 1, 2002; 22(4): 599 - 604. [Abstract] [Full Text] [PDF]
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W. Shi, X. Wang, K. Tangchitpiyanond, J. Wong, Y. Shi, and A. J. Lusis Atherosclerosis in C3H/HeJ Mice Reconstituted With Apolipoprotein E-Null Bone Marrow Arterioscler Thromb Vasc Biol, April 1, 2002; 22(4): 650 - 655. [Abstract] [Full Text] [PDF]
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A. Hockerstedt, M. J. Tikkanen, and M. Jauhiainen LCAT facilitates transacylation of 17{beta}-estradiol in the presence of HDL3 subfraction J. Lipid Res., March 1, 2002; 43(3): 392 - 397. [Abstract] [Full Text] [PDF]
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G.F. Gensini and B. Dilaghi The unstable plaque Eur. Heart J. Suppl., March 1, 2002; 4(suppl_B): B22 - B27. [Abstract] [PDF]
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G. Subbanagounder, J. W. Wong, H. Lee, K. F. Faull, E. Miller, J. L. Witztum, and J. A. Berliner Epoxyisoprostane and Epoxycyclopentenone Phospholipids Regulate Monocyte Chemotactic Protein-1 and Interleukin-8 Synthesis. FORMATION OF THESE OXIDIZED PHOSPHOLIPIDS IN RESPONSE TO INTERLEUKIN-1beta J. Biol. Chem., February 22, 2002; 277(9): 7271 - 7281. [Abstract] [Full Text] [PDF]
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G. Arcaro, A. Cretti, S. Balzano, A. Lechi, M. Muggeo, E. Bonora, and R. C. Bonadonna Insulin Causes Endothelial Dysfunction in Humans: Sites and Mechanisms Circulation, February 5, 2002; 105(5): 576 - 582. [Abstract] [Full Text] [PDF]
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Y. Tintut, J. Patel, M. Territo, T. Saini, F. Parhami, and L. L. Demer Monocyte/Macrophage Regulation of Vascular Calcification In Vitro Circulation, February 5, 2002; 105(5): 650 - 655. [Abstract] [Full Text] [PDF]
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 Y. Bulut, E. Faure, L. Thomas, H. Karahashi, K. S. Michelsen, O. Equils, S. G. Morrison, R. P. Morrison, and M. Arditi Chlamydial Heat Shock Protein 60 Activates Macrophages and Endothelial Cells Through Toll-Like Receptor 4 and MD2 in a MyD88-Dependent Pathway J. Immunol., February 1, 2002; 168(3): 1435 - 1440. [Abstract] [Full Text] [PDF]
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Z.-B. Lei, Z. Zhang, Q. Jing, Y.-W. Qin, G. Pei, B.-Z. Cao, and X.-Y. Li OxLDL upregulates CXCR2 expression in monocytes via scavenger receptors and activation of p38 mitogen-activated protein kinase Cardiovasc Res, February 1, 2002; 53(2): 524 - 532. [Abstract] [Full Text] [PDF]
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 A. Steptoe and M. Marmot The role of psychobiological pathways in socio-economic inequalities in cardiovascular disease risk Eur. Heart J., January 1, 2002; 23(1): 13 - 25. [Full Text] [PDF]
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H. Kamido, H. Eguchi, H. Ikeda, T. Imaizumi, K. Yamana, K. Hartvigsen, A. Ravandi, and A. Kuksis Core aldehydes of alkyl glycerophosphocholines in atheroma induce platelet aggregation and inhibit endothelium-dependent arterial relaxation J. Lipid Res., January 1, 2002; 43(1): 158 - 166. [Abstract] [Full Text] [PDF]
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M. Toborek, Y. W. Lee, R. Garrido, S. Kaiser, and B. Hennig Unsaturated fatty acids selectively induce an inflammatory environment in human endothelial cells Am. J. Clinical Nutrition, January 1, 2002; 75(1): 119 - 125. [Abstract] [Full Text] [PDF]
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