Arteriosclerosis, Thrombosis, and Vascular Biology. 1995;15:551-561
(Arteriosclerosis, Thrombosis, and Vascular Biology. 1995;15:551-561.)
© 1995 American Heart Association, Inc.
The Response-to-Retention Hypothesis of Early Atherogenesis
Kevin Jon Williams;
Ira Tabas
From the Division of Endocrinology and Metabolic Diseases, Thomas
Jefferson University, Philadelphia, Pa (K.J.W.), and the Departments of
Medicine and Anatomy and Cell Biology, Columbia University, New York, NY
(I.T.).
Correspondence to Kevin Jon Williams, MD, Division of Endocrinology and Metabolic Diseases, Thomas Jefferson University, Jefferson Alumni Hall, Suite 349, 1020 Locust St, Philadelphia, PA 19107-6799. E-mail k_williams@lac.jci.tju.edu.
 |
Introduction
|
|---|
Many processes have been implicated in
early atherogenesis.
These include endothelial denudation, injury, or
activation,
including shear stressrelated events; local adherence
of
platelets; lipoprotein oxidation; lipoprotein aggregation;
macrophage
chemotaxis and foam cell formation; and smooth muscle
cell alterations.
Which process, if any, could be regarded as
the key event in early
atherogenesis, ie, absolutely required,
yet also sufficient as the sole
pathological stimulus in an
otherwise normal artery to provoke a
cascade of events leading
to lesion formation? The work of many
investigators, which we
summarize here, strongly supports
subendothelial retention of
atherogenic lipoproteins as the central
pathogenic process in
atherogenesis (for prior reviews, see References
1 through 6
1 2 3 4 5 6 ). Our thesis is that other contributory processes
are
either not individually necessary or are not sufficient.
Most often,
they are merely normal, expected responses of otherwise-healthy
tissue
to the presence of retained lipoproteins.
 |
Competing Hypotheses
|
|---|
It is instructive to catalog other processes that have been
argued
to be central to the initiation of atherogenesis. The
first is
endothelial denudation,
7 8 9 injury,
10 or
activation,
11 12 as outlined in the
"response-to-injury" hypothesis of Ross,
Glomset, and coworkers.
Although this important hypothesis has
stimulated much of the work that
we cite here, there is no definitive
evidence in vivo that endothelial
injury is either necessary
or sufficient for lesion formation.
The response-to-injury hypothesis originally presupposed endothelial
desquamation as the key event in atherogenesis.7 8 9 It is
now clear, however, that developing atheromata are covered by an intact
endothelial layer throughout most stages of lesion progression:
lipoprotein retention, fatty streak formation, and formation of
advanced lesions.5 6 12 13 14 15 In humans, only the most
complicated, ulcerated lesions lose their endothelial layer.
Furthermore, in some experimental models, an intact endothelium is
required for lesion initiation and development, which do not occur in
adjacent areas of denudation.16 17 18 Gross endothelial
denudation, though presumably important in restenosis after balloon
injury19 and in very advanced complicated plaques, does
not appear to be central to early atherogenesis.5
A refinement of the response-to-injury hypothesis states that
endothelial injuries that are insufficient to cause gross denudation
but severe enough to cause functional modifications are key to
atherogenesis.10 11 12 20 A major hypothesized change in
endothelial function was increased permeability,21 22
particularly to atherogenic lipoproteins.23 24 25 26 27 This idea
is related to the lipid infiltration hypothesis,5 which
originated with Anichkov and Khalatov28 (reviewed in
References 29 and 3029 30 ). Alterations in permeability or even microscopic
losses of endothelial cells in excess of those due to normal cell
turnover are not mechanistically required for atherogenesis, however,
because normal, healthy endothelium transports31 32 or
"leaks"26 33 many molecules, including lipoproteins
(reviewed in Reference 2727 ). In fact, the rate of LDL entry into the
normal, healthy arterial wall vastly exceeds the LDL accumulation
rate.34 Most important, seminal studies by Schwenke and
Carew35 36 showed in vivo that the early prelesional
accumulation of atherogenic lipoproteins within the arterial wall is
focally concentrated in sites that are known to be prone to the later
development of atheromata, but that the rates of lipoprotein entry into
prelesional susceptible versus resistant sites were not different (cf
Reference 22 ). These studies indicate that retention, not enhanced
endothelial permeability to lipoprotein influx, is the key pathological
event in this experimental model. Subsequent studies in several other
animal models have demonstrated either increased23 24 25 26 or
decreased37 rates of lipoprotein entry into
atherosclerosis-susceptible sites, suggesting a nonessential role for
alterations in endothelial permeability. All studies agree, however,
that prelesional susceptible arterial sites show enhanced retention of
apoB-rich, atherogenic lipoproteins.35 36 38 39 40 41 We
conclude that alterations in endothelial permeability, though
apparently not essential to lesion development, may play a contributory
role, eg, in smoking,42 dyslipidemias27 37
(cf Reference 3636 ), and possibly hypertension27 (cf
Reference 4343 ), but only if some of the infiltrated material is
retained.35
Several other functional modifications have been documented in the
endothelial layer in vivo during atherogenesis, but these occur
comparatively late. For example, in rabbits, cell adhesion
molecules,44 the earliest known being vascular cell
adhesion molecule1 (VCAM-1), are expressed by endothelial cells
that overlie lesions, but only after more than 4 days of severe
hypercholesterolemia and resultant foam cell formation.45
In contrast, lipoprotein retention and aggregation are detectable
within minutes to hours after the onset of
hypercholesterolemia.31 36 41 46 Furthermore, atherogenic
lipoproteins and their components have been shown to regulate
endothelial expression of cell-adhesion molecules.12 47 48 49
The most straightforward conclusion is that the earliest known
endothelial changes during atherogenesis in vivo, such as VCAM-1
expression, cannot be a cause, and are likely to be a consequence, of
the initial retention of lipoproteins within the arterial wall (see
"Future Directions").
The effect of turbulent blood flow on the arterial wall deserves
special comment, particularly because it can be such an early
influence. Arterial segments that are subject to turbulent blood flow,
such as those at branch points or during hypertension, show a
predisposition to lesion development, though the precise relationship
in vivo may be complicated.50 Because of the
response-to-injury hypothesis, the connection between blood flow and
atherogenesis has led to many studies on the effects of shear stress on
the endothelium in cell culture experiments. Many alterations have been
reported,12 18 51 such as intracellular calcium
mobilization, ion channel activation, cytoskeletal changes, altered
cellular alignment, cell surface streamlining,52 increased
endothelial cell division,53 stimulation of specific
transcription factors,54 and production of potentially
atherogenic molecules, such as vasoactive,55
adhesive,56 and growth12 20 57 factors.
Somewhat different results are obtained in vitro when shear is low
instead of high, constant instead of pulsatile, laminar instead of
turbulent, or spatially uniform instead of graded,12 51 53
but the overall findings in vitro strongly support a contributory role
for shear stressinduced alterations of the endothelium during
atherogenesis.
In vivo, however, it is clear that sheer stressinduced
endothelial alterations are neither necessary nor sufficient for
atherogenesis. In vivo lesion development at sites of turbulent flow
shows an absolute requirement for high plasma concentrations of
atherogenic lipoproteins relative to those that occur naturally in
nonhuman, nonatherosclerotic mammals: the plasma concentration of LDL
cholesterol must exceed 2 mmol/L (80 mg/dL) for atherogenesis, even at
sites of high shear stress.58 59 Furthermore, at
sufficiently high plasma lipoprotein concentrations, lesions develop
even at sites of low shear stress, such as at nonbranch
points6 60 or within the pulmonary
arteries.60 61 Although stress-induced endothelial changes
can play a contributory role in atherogenesis, the most directly
relevant functional changes that have been documented at prelesional
sites that are susceptible to atherogenesis, including those that are
subject to turbulent blood flow, are altered proteoglycan
structure62 63 64 65 66 and increased lipoprotein
retention36 39 46 67 68 69 (see above).
We therefore propose that the atherogenic effects of sheer stress in
vivo are entirely dependent on lipoprotein retention within the
arterial wall and are limited to increased local vulnerability to
lipoprotein retention and the consequences thereof. Specifically, we
hypothesize that the role of shear stress in early atherogenesis is
mediated primarily through the stimulation of intramural synthesis of
molecules, such as proteoglycans, that promote lipoprotein retention
(see References 63, 64, 66, 70, and 7163 64 66 70 71 ). Later, once vessel segments
have accumulated retained lipoproteins, the threshold for injury and
activation from continued shear stress may be lowered. Many stimuli can
activate endothelial cells, and synergy is likely between shear stress
and, for example, oxidative breakdown products of retained
lipoproteins. The same general lines of reasoning can be used to argue
against a central role for other potential activators of the
endothelium, such as viruses72 or
homocysteine,9 12 20 73 which are likewise neither
necessary nor sufficient for lesion development in vivo. Note that
these hypotheses about the central role of retained lipoproteins are
testable (see "Future Directions").
The second process that has been proposed to be central to
atherogenesis is lipoprotein oxidation.74 75 76 Current
evidence indicates, however, that pathophysiologically important
oxidation can occur only after the retention of lipoproteins within the
sequestered microenvironment of the arterial wall. Lipoprotein
oxidation by cells or transition metals in vitro is blocked by small
concentrations of plasma or plasma proteins,77 such as
albumin78 79 80 81 82 83 (cf Reference 8484 ), and any oxidized
lipoproteins that might appear in the plasma in vivo would be rapidly
removed by the liver,85 86 rather than be deposited into
developing lesions within the arterial wall.87 In fact,
oxidation may be regarded as a normal, expected consequence of
lipoprotein trapping: studies in vitro indicate that once lipoproteins
are sequestered from the protective elements of plasma, nearby healthy
arterial cells will cause oxidation,75 apparently through
their efficient generation of thiols.88 89 In vivo,
myeloperoxidases may be involved.90 Note that adherence of
LDL to arterial proteoglycans increases LDL's susceptibility to
oxidation in vitro71 91 (see below), but that prior
oxidation of LDL does not enhance its retention in
arteries.87 Consistent with these results, apoB is
retained in the human intima before it is detectably
oxidized.92 The most straightforward conclusion is that
oxidation is a normal, expected consequence of intramural sequestration
of sufficient quantities of atherogenic lipoproteins within an
otherwise healthy artery.
The importance of lipoprotein oxidation in lesion development is
supported by discoveries of many biological consequences in vitro that
are consistent with atherogenesis,48 74 75 93 by
demonstrations of antiatherogenic effects in experimental animals of
compounds with antioxidant actions,94 95 96 and by the
findings in humans of oxidized epitopes within
lesions92 97 (see Reference 9898 ) and of antioxidized LDL
antibodies within lesions99 and in plasma.100
Nevertheless, there are also reports that show the ineffectiveness of
antioxidants on atherogenesis. For example, recent reports of humans
who consumed antioxidant vitamins101 102 or who were given
probucol103 104 and of animals that were given a potent
antioxidant analogue of probucol that does not affect plasma
lipoprotein concentrations105 106 (see Reference 107107 )
failed to find beneficial effects of these treatments on disease. Note
that vitamin E and probucol, which appear to be antiatherogenic in
humans102 and animals,94 95 respectively,
have many actions besides inhibition of lipoprotein
oxidation.102 104 105 108 109 Because even minimal
oxidation of LDL, which has been described in human
lesions110 (see also Reference 111111 ), produces many
potentially harmful biological effects,93 lipoprotein
oxidation is unlikely to be a rate-limiting step in atherogenesis.
Thus, nearly total inhibition of oxidation of retained lipoproteins may
be required before there would be any substantial effect on lesion
development in vivo (cf Reference 105105 ).
 |
Evidence to Support Retention as the Key Event
|
|---|
Following rapid induction of hypercholesterolemia in rabbits
due
to injection of LDL, the earliest detectable change in the
arterial
wall is the intramural retention of LDL and of microaggregates
of LDL,
a change that occurs within 2 hours.
46 Perfusion of
arterial
segments in situ has shown substantial accumulation of LDL
within
5 minutes.
31 Early arterial retention of injected
LDL in vivo
is focal, in sites that are known to be susceptible to the
subsequent
development of atheromata.
35 36 LDL retention
in these sites
is not the result of increased flux into the arterial
wall but
from reduced lipoprotein egress.
36 These rapidly
apparent differences
in lipoprotein retention between prelesional
susceptible versus
resistant sites suggest a preexisting metabolic
difference that,
under the proper conditions of hypercholesterolemia,
leads to
differences in lipoprotein retention. This conclusion is
supported
by the observation that atherosclerosis cannot develop when
plasma
ß-lipoprotein concentrations are truly
low,
58 59 112 even in the presence of other major risk
factors.
113
Several lines of evidence indicate that intramural retention of
atherogenic lipoproteins involves extracellular matrix, chiefly
proteoglycans1 71 and perhaps other structural
elements,114 115 116 117 118 119 and lipolytic enzymes, chiefly
lipoprotein lipase (LpL)120 121 122 123 124 125 126 127 and sphingomyelinase
(SMase).127 128 129 130 First, all of these molecules are
present to varying degrees within the normal arterial
wall.70 71 120 128 131 132 133 Thus, they are available to
participate in the earliest stages of atherogenesis. Second, retained
apoB in extremely early46 69 as well as
advanced64 71 lesions is closely associated with arterial
proteoglycans. Purified arterial proteoglycans, particularly those from
lesion-prone sites,66 134 bind LDL in vitro, particularly
LDL from patients with coronary artery disease.135 136
This interaction involves several well-defined, positively charged
segments of apoB.71 137 Third, LpL enhances adherence of
LDL in vitro to the matrix that is derived from normal
endothelial125 138 and smooth muscle127 cells
and to normal cell-surface proteoglycans.122 123 124 125 126 127 139 This
adherence is independent of LpL enzymatic
activity122 123 125 127 (cf References 120 and 121120 121 ) and
appears to occur in vessels enriched in situ with LpL.140
Fourth, a linkage between peritoneal macrophage production of LpL and
susceptibility to atherosclerosis has been documented in recombinant
inbred mice.141 Results in humans indicate a linkage
between LpL polymorphisms and coronary artery disease, though without a
linkage between LpL polymorphisms and specific plasma lipoprotein
patterns, thus suggesting that the effects on lesion development are
independent of plasma changes.142 A genetic absence of LpL
in humans has long been known to cause hyperlipidemia without increased
atherosclerosis,121 presumably because of poor generation
of small, cholesteryl esterrich particles143 that are
able to enter the arterial wall27 and loss of
LpL-facilitated binding to arterial proteoglycans.122 123 124 125 126 127
More recent work in humans indicates that the single most important
determinant of lesion development in homozygous familial
hypercholesterolemia is the postheparin plasma concentration of LpL
mass, not enzymatic activity; this is consistent with a structural
effect.144 Fifth, SMase causes the formation of LDL
microaggregates129 that morphologically resemble the
intramural particles seen 2 hours after rapid induction of
hypercholesterolemia,46 and LpL and SMase synergistically
interact to cause massive retention and aggregation of LDL and Lp(a) in
vitro to arterial cell proteoglycans and matrix.127 The
arterial wall SMase128 was recently shown to act on the
LDL retained in aortic strips ex vivo.130 At later stages,
once atherogenesis has begun, the content of specific
proteoglycans,64 65 66 71 145
LpL,120 131 132 133 146 147 148 and SMase128
increases in lesional areas, thereby apparently accelerating the
disease.
The factors responsible for focal retention of lipoproteins and
subsequent lesion development, however, are not clear. Because
prelesional differences in lipoprotein retention between susceptible
versus resistant arterial sites are so rapidly apparent after induction
of hypercholesterolemia,35 there are likely to be
preexisting local differences in apoB-retentive molecules. Proteoglycan
variations alone may not explain the focal development of early
lesions, because potentially atherogenic proteoglycans are abundant and
ubiquitous throughout the arterial tree,70 though focal
alterations in proteoglycans have been documented in
prelesional63 64 65 66 and lesional145 149 sites.
The enzymes LpL and SMase show enhanced expression in established
human133 146 148 and animal133 lesions, and
arterial contents of LpL were shown two decades ago to correlate
strongly with the arterial accumulation of cholesteryl ester during
atherogenesis in rabbits (r=0.9).121
Nevertheless, the status of proteoglycans, LpL, SMase, and possibly
other apoB-retentive molecules in prelesional susceptible versus
prelesional resistant sites remains an important area for study (see
"Future Directions").
 |
Consequences of Retention
|
|---|
Following its retention by proteoglycans, LDL has been shown
in
vitro to undergo several modifications with important biological
consequences.
Proteoglycan-bound LDL in vitro forms
aggregates
71 and vesicular
structures
127 that
resemble material seen in vivo.
46 67 68 150 151
LDL-proteoglycan complexes show increased susceptibility
to
oxidation under typical serum-free, albumin-free pro-oxidative
experimental
conditions.
91 Minimally oxidized LDL induces
endothelial and
smooth muscle cells to express monocyte chemotactic
activity,
152 and more extensively oxidized LDL is directly
chemoattractive
to monocytes,
153 154 smooth muscle
cells,
155 and T lymphocytes,
154 largely
because of its lysophosphatidylcholine content.
154
Retained LDL would also be subject to arterial wall
SMases,
127 128 129 130 which generate choline phosphate and
ceramides.
Ceramides are well documented to have many biological
effects,
such as induction of NF-

B and stimulation of apoptosis or
mitogenesis.
156 157
LDL that has been aggregated or otherwise modified by arterial
proteoglycans under a variety of conditions in vitro is avidly taken up
by normal cultured macrophages and smooth muscle cells,134
leading to foam cell formation.136 151 158 This avid
uptake may involve several different
receptors,122 123 124 125 126 134 139 158 159 of which only the LDL
receptors are known to be nonessential, in that their genetic absence
does not impede arterial lipoprotein accumulation160 or
atherogenesis60 161 in vivo, in contrast to the situation
with LpL deficiency (see above). The conversion of macrophages to foam
cells stimulates the release of more
LpL133 146 147 148 162 163 and other potentially atherogenic
factors164 165 166 and has been shown to alter proteoglycan
metabolism.167 Retained, altered
lipoproteins155 168 169 and nearby
macrophages170 171 can stimulate chemotaxis and
transformation of smooth muscle cells from the contractile to the
proliferative state, which in smooth muscle cells causes increased
synthesis of proteoglycans,64 172 including LDL-binding
proteoglycans,173 and possibly LpL132 133 (cf
Reference 146146 ). Thus, retained lipoproteins can directly or indirectly
provoke all known features of early lesions and, by stimulating local
synthesis of proteoglycans and LpL, can accelerate further lipoprotein
retention and aggregation.
Lesion development may be altered by local cellular expression of apoE
within the arterial wall. As macrophages become foam cells in situ,
they appear to increase their synthesis of apoE,148 174 a
molecule that has been shown in vitro to release lipoproteins from the
extracellular matrix175 (see Reference 137137 ). The ultimate
fate of these released lipoproteins, however, is unclear. They
could leave the lesion, or they could be taken up by arterial cells,
particularly through apoE-mediated binding.
The atherogenic nature of Lp(a) may originate from its
extensive propensity for intramural
retention.41 136 176 177 178 Despite plasma
concentrations of Lp(a) that are far lower than those of other
apoB-rich lipoproteins, Lp(a) may account for most of the apoB in human
lesions.179 180 In vitro, Lp(a) binds to arterial
proteoglycans with greater affinity176 and
capacity176 181 than does LDL. Avid cellular uptake of
Lp(a) by at least four processes may then occur: through scavenger
receptors after oxidation86 ; through the heparan
sulfateproteoglycan pathway in the presence of intramural
LpL122 123 ; by phagocytosis following aggregation and
cross-linking by LpL, SMase, and proteoglycans127 ; and by
a specific Lp(a)/apo(a) receptor on cholesterol-enriched
macrophages.182 183 After Lp(a) retention, many other
biological effects occur, including enhanced LDL
retention,184 stimulation of smooth muscle cell
proliferation,185 and, possibly, local inhibition of lysis
of microthrombi186 187 188 189 (cf References 190 through
192190 191 192 ).
 |
Future Directions
|
|---|
A major mystery in atherogenesis is the well-known variation
in
lesion progression among individuals with similar plasma
lipid profiles
(see Reference 59
59 ) and among different arterial
sites within the same
individual.
6 All known risk factors account
for merely
50% of coronary events and well under 50% of interindividual
variability
in the actual extent of coronary lesions.
193
The remaining
risk is at least partially attributable to poorly
characterized
properties of the vessel wall. The response-to-retention
hypothesis
predicts that these vessel wall factors include molecules
involved
in lipoprotein retention, which, at this state of our
knowledge,
means proteoglycans, LpL, SMase, apoE, apoB, and apo(a).
Tools now exist or can be developed to assess the roles of
proteoglycans and arterial wall enzymes in very early atherogenesis.
Many proteoglycan core proteins of endothelial194 195 196 and
smooth muscle194 195 197 198 199 200 201 202 cells have been cloned and
sequenced, which would allow linkage studies in animals and humans and
direct genetic manipulation, particularly at lesion-susceptible branch
points. Enzymes that are involved in proteoglycan side-chain assembly
are still being characterized,203 204 205 206 but we suggest that
polymorphisms might play a role in atherosclerosis susceptibility (see
References 207 and 208207 208 ). To establish a causal role for LpL in
atherogenesis in vivo, direct stimulation and especially suppression of
intramural arterial LpL must be done, followed by an examination of
lesion progression (see Reference 140140 ). Because several functional
domains within LpL have already been characterized,209
specific constructs can be engineered to separately examine in vivo the
atherogenicity of its enzymatic121 versus
structural122 123 125 127 actions. Two decades ago,
lesions were shown to be enriched with SMase, but detailed enzymatic or
molecular characterization of this lipase activity is still lacking,
thus preventing linkage studies or genetic manipulation. The mechanism
of SMase-induced aggregation in vitro has been shown to depend on the
generation of ceramide.130 Thus, to implicate SMase
in atherogenesis, lesional lipoproteins will have to be shown to
be enriched in ceramide.
Investigation into the local roles of apoproteins and other molecules
in very early atherogenesis can also be performed. Transgenic mice that
overexpress apoE in the arterial wall, among other sites, have shown
reduced atherosclerosis in one preliminary report,210
consistent with the hypothesis of a local protective role for this
molecule in vivo.175 211 Transgenic mice that overexpress
apoA-I show reduced lesion development,212 213 214 perhaps
because of accelerated reverse cholesterol transport, but possibly
because of the local inhibitory effects that apoA-I particles exert on
aggregation215 216 and
oxidation77 80 84 215 217 of atherogenic lipoproteins. It
will be interesting to develop animal models in which overexpression of
apoE or apoA-I is cleanly confined to the arterial wall. The physical
characteristics of LDL, including its size,218 219 apoB
conformation,220 or sialic acid content,221
may affect binding affinity to arterial
proteoglycans135 219 221 and subsequent
oxidation.220 222 Apo(a) polymorphisms177
should also be examined.
Tools exist as well to investigate the proposed sequence of events in
early atherogenesis, subsequent to lipoprotein retention. For example,
on the basis of the apparent sequence of events in vivo, we predict
that massive retention of LDL or Lp(a) by smooth muscle cells or
matrix127 will stimulate nearby endothelial and possibly
smooth muscle cells127 152 223 to express cell adhesion
molecules, chemoattractants, and growth factors (see "Competing
Hypotheses"). A likely mechanism would be oxidation of the retained
lipoproteins, followed by release of biologically active components,
such as lysophosphatidylcholine, which is known to stimulate the
expression of VCAM-1, platelet-derived growth factor, and other
molecules by otherwise-normal endothelium.224 The
prediction can be tested by coculture in vitro,84 with
specific emphasis on the search for lipoprotein retention as an initial
event. In addition, we predict that one key atherogenic effect of
turbulent blood flow on prelesional sites in vivo is the locally
enhanced expression of apoB-retaining molecules, particularly by
vascular smooth muscle cells. A search for these molecules in
susceptible versus resistant prelesional arterial sites could be
undertaken, the molecules genetically manipulated if already cloned,
and the effects on atherogenesis examined. Possible mechanisms for
altered expression of these molecules would include direct effects of
hemodynamic forces acting through sheer stress responseelements in
underlying smooth muscle cells18 or through
endothelium-dependent effects,63 including
direct electrical communication between the endothelium and smooth
muscle18 225 or humoral signals.63 For
example, transforming growth factorß is expressed by the
endothelium under control of a shear stressresponsive
element57 and is known to stimulate synthesis of
chondroitin sulfate proteoglycans by smooth muscle
cells.226 227
Finally, the search for additional molecules or mechanisms that may be
important in vivo to lipoprotein retention and responses to retention
should continue. For example, collagen,114
fibrin,115 116 fibronectin,117 118 119 and
matrix-bound phospholipase A2228 229 have been
implicated in several studies. Also, the LDL receptorrelated protein,
which binds LpL230 and apoE231 on ligand
blots in vitro, has recently been reported to be present in normal
and lesional arteries.232 233 Of particular interest is
how an arterial segment might remain healthy after the entry of
lipoproteins (see Reference 9292 ). For example, there is substantial and
well-documented evidence for the egress of atherogenic lipoproteins
from the normal arterial wall,27 36 which has generally
been assumed to be passive, though it may not be. Other processes that
could blunt or enhance oxidative and inflammatory responses to retained
lipoproteins show genetic variability in mice234 and merit
further study in humans.
Arterial retention of atherogenic lipoproteins is a logical target for
therapeutic intervention. So far, three strategies specifically
directed against lipoprotein retention have been proposed in the
literature. The first strategy is the local use of molecules that
interfere with adherence of apoB or apo(a)-apoB to arterial
proteoglycans. As noted before, apoE is a promising candidate, in
vitro137 175 and possibly in mice.210
Boosting local expression of apoE in human arterial segments, however,
would be difficult at present and may require gene therapy, an
approach still in its infancy. Other potential candidates include apoB
fragments137 or other proteoglycan-binding
peptides.235 236 237 The second strategy proposed in the
literature is inhibition of intra-arterial SMase
activity.129 The effects of SMase, unlike the effect of
LpL, involve its enzymatic action.130 Specific enzymatic
inhibitors could test its role in vivo and might provide therapeutic
benefit. A third strategy to reduce arterial retention of LDL is the
use of nifedipine,238 a calcium-channel blocker that
alters many cellular functions,239 including arterial
retention of autologous, but not human, LDL in normocholesterolemic
rabbits.238 Note, however, that calcium-channel blockers
do not appear to affect atherogenesis in LDL receptordeficient
rabbits, which exhibit nondietary hyperlipidemia.240 Other
novel targets to consider would be inhibition of intramural production
of proteoglycans or LpL, alteration of cytokine expression, such as
transforming growth factorß, and perhaps stimulation of ceramidase
production.
 |
Concluding Remarks
|
|---|
Although atherosclerosis is a complex and multifactorial process,
we
conclude that there exists a key pathogenic event, namely,
lipoprotein
retention, that is both necessary and sufficient to provoke
lesion
initiation in an otherwise-normal artery. Other potential
contributors
to early atherogenesis, such as hyperlipidemia;
lipoprotein
influx; lipoprotein modification; turbulent blood flow; and
alterations
in the endothelium, smooth muscle cells, and matrix,
individually
fail to meet this dual criterion of necessity and
sufficiency.
Lipoprotein retention, however, is an absolute requirement
for
lesion development and appears to be sufficient in most
circumstances
to provoke otherwise-normal cellular and matrix elements
to
participate in a cascade of events leading to atherosclerosis
(see
the Figure

). Essentially all later events can be traced
to
these early changes.

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|
Figure 1. Schematic of the response-to-retention model of early
atherogenesis. Mild to moderate hyperlipidemia causes lesion
development only in specific sites within the arterial tree, implying
the existence of predisposing stimuli, such as sheer stress, that make
these sites particularly lesion-prone by stimulating local synthesis of
apoB-retentive molecules (B). Predisposing stimuli in the absence of
abundant atherogenic lipoproteins (ie, <2 mmol LDL cholesterol/L) are
insufficient to cause atherogenesis. Predisposing stimuli in the
presence of abundant atherogenic lipoproteins result in lipoprotein
retention (C). Evidence suggests that aggregation promptly follows or
may be part of the retentive process. Once significant retention has
occurred, a cascade of early responses, including lipoprotein oxidation
and cellular chemotaxis, leads to lesion development (D). ECs indicates
endothelial cells; PGs, proteoglycans; IEL, internal elastic lamina;
SMCs, smooth muscle cells; LpL, lipoprotein lipase; SMase,
sphingomyelinase; and LPs, lipoproteins.
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|
 |
Acknowledgments
|
|---|
Dr Williams is an Established Investigator of the American Heart
Association
and Genentech. During portions of this work, Dr Tabas was
an
Established Investigator of the American Heart Association and
Boehringer-Ingelheim.
Support is also acknowledged from National
Institutes of Health
grants HL38956, HL39703, and HL21006 and a
cardiovascular research
grant from the W.W. Smith Charitable Trust. We
thank our colleagues
for their helpful comments during the preparation
of this article.
Received December 5, 1994;
accepted February 21, 1995.
 |
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