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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1995;15:551-561.)
© 1995 American Heart Association, Inc.

Articles

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

Top Introduction Competing Hypotheses Evidence to Support Retention... Consequences of Retention Future Directions Concluding Remarks References

 
Many processes have been implicated in early atherogenesis. These include endothelial denudation, injury, or activation, including shear stress–related 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

Top Introduction Competing Hypotheses Evidence to Support Retention... Consequences of Retention Future Directions Concluding Remarks References

 
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 30^{29 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 transports^{31 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 Carew^{35 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 increased^{23 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 dyslipidemias^{27 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 molecule–1 (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 growth^{12 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 stress–induced alterations of the endothelium during atherogenesis.

In vivo, however, it is clear that sheer stress–induced 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 non–branch points^{6 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 structure^{62 63 64 65 66} and increased lipoprotein retention^{36 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 71^{63 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 albumin^{78 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 vitro^{71 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 lesions^{92 97} (see Reference 98⁹⁸ ) and of anti–oxidized 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 vitamins^{101 102} or who were given probucol^{103 104} and of animals that were given a potent antioxidant analogue of probucol that does not affect plasma lipoprotein concentrations^{105 106} (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

Top Introduction Competing Hypotheses Evidence to Support Retention... Consequences of Retention Future Directions Concluding Remarks References

 
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 proteoglycans^{1 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 early^{46 69} as well as advanced^{64 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 endothelial^{125 138} and smooth muscle¹²⁷ cells and to normal cell-surface proteoglycans.^{122 123 124 125 126 127 139} This adherence is independent of LpL enzymatic activity^{122 123 125 127} (cf References 120 and 121^{120 121} ) 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 ester–rich 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 prelesional^{63 64 65 66} and lesional^{145 149} sites. The enzymes LpL and SMase show enhanced expression in established human^{133 146 148} 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

Top Introduction Competing Hypotheses Evidence to Support Retention... Consequences of Retention Future Directions Concluding Remarks References

 
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 aggregates⁷¹ and vesicular structures¹²⁷ 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 atherogenesis^{60 161} in vivo, in contrast to the situation with LpL deficiency (see above). The conversion of macrophages to foam cells stimulates the release of more LpL^{133 146 147 148 162 163} and other potentially atherogenic factors^{164 165 166} and has been shown to alter proteoglycan metabolism.¹⁶⁷ Retained, altered lipoproteins^{155 168 169} and nearby macrophages^{170 171} 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 LpL^{132 133} (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 capacity^{176 181} 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 sulfate–proteoglycan pathway in the presence of intramural LpL^{122 123} ; 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 microthrombi^{186 187 188 189} (cf References 190 through 192^{190 191 192} ).

	Future Directions

Top Introduction Competing Hypotheses Evidence to Support Retention... Consequences of Retention Future Directions Concluding Remarks References

 
A major mystery in atherogenesis is the well-known variation in lesion progression among individuals with similar plasma lipid profiles (see Reference 59⁵⁹ ) 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 endothelial^{194 195 196} and smooth muscle^{194 195 197 198 199 200 201 202} 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 208^{207 208} ). 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 structural^{122 123 125 127} 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 aggregation^{215 216} and oxidation^{77 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 proteoglycans^{135 219 221} 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 cells^{127 152 223} 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 response–elements in underlying smooth muscle cells¹⁸ or through endothelium-dependent effects,⁶³ including direct electrical communication between the endothelium and smooth muscle^{18 225} or humoral signals.⁶³ For example, transforming growth factor–ß is expressed by the endothelium under control of a shear stress–responsive 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 A₂^{228 229} have been implicated in several studies. Also, the LDL receptor–related 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 vitro^{137 175} 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 receptor–deficient 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 factor–ß, and perhaps stimulation of ceramidase production.

	Concluding Remarks

Top Introduction Competing Hypotheses Evidence to Support Retention... Consequences of Retention Future Directions Concluding Remarks References

 
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.

View larger version (2K): [in this window] [in a new window]   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.

	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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				J. J. Manning-Tobin, K. J. Moore, T. A. Seimon, S. A. Bell, M. Sharuk, J. I. Alvarez-Leite, M. P.J. de Winther, I. Tabas, and M. W. Freeman Loss of SR-A and CD36 Activity Reduces Atherosclerotic Lesion Complexity Without Abrogating Foam Cell Formation in Hyperlipidemic Mice Arterioscler. Thromb. Vasc. Biol., January 1, 2009; 29(1): 19 - 26. [Abstract] [Full Text] [PDF]

				H. Samyn, M. Moerland, T. van Gent, R. van Haperen, J. Metso, F. Grosveld, M. Jauhiainen, A. van Tol, and R. de Crom Plasma phospholipid transfer activity is essential for increased atherogenesis in PLTP transgenic mice: a mutation-inactivation study J. Lipid Res., December 1, 2008; 49(12): 2504 - 2512. [Abstract] [Full Text] [PDF]

				P. G. Wilson, J. C. Thompson, N. R. Webb, F. C. de Beer, V. L. King, and L. R. Tannock Serum Amyloid A, but Not C-Reactive Protein, Stimulates Vascular Proteoglycan Synthesis in a Pro-Atherogenic Manner Am. J. Pathol., December 1, 2008; 173(6): 1902 - 1910. [Abstract] [Full Text] [PDF]

				A. Afaq, P. S. Montgomery, K. J. Scott, S. M. Blevins, T. L. Whitsett, and A. W. Gardner The Effect of Hypercholestrolemia on Calf Muscle Hemoglobin Oxygen Saturation in Patients With Intermittent Claudication Angiology, October 1, 2008; 59(5): 534 - 541. [Abstract] [PDF]

				C. M. Devlin, A. R. Leventhal, G. Kuriakose, E. H. Schuchman, K. J. Williams, and I. Tabas Acid Sphingomyelinase Promotes Lipoprotein Retention Within Early Atheromata and Accelerates Lesion Progression Arterioscler. Thromb. Vasc. Biol., October 1, 2008; 28(10): 1723 - 1730. [Abstract] [Full Text] [PDF]

				A. M. Greve and K. Wachtell Review: Does lowering cholesterol have an impact on the progression of aortic stenosis? Therapeutic Advances in Cardiovascular Disease, August 1, 2008; 2(4): 277 - 286. [Abstract] [PDF]

				K. Tran-Lundmark, P.-K. Tran, G. Paulsson-Berne, V. Friden, R. Soininen, K. Tryggvason, T. N. Wight, M. G. Kinsella, J. Boren, and U. Hedin Heparan Sulfate in Perlecan Promotes Mouse Atherosclerosis: Roles in Lipid Permeability, Lipid Retention, and Smooth Muscle Cell Proliferation Circ. Res., July 3, 2008; 103(1): 43 - 52. [Abstract] [Full Text] [PDF]

				Y. Nakashima, T. N. Wight, and K. Sueishi Early atherosclerosis in humans: role of diffuse intimal thickening and extracellular matrix proteoglycans Cardiovasc Res, July 1, 2008; 79(1): 14 - 23. [Abstract] [Full Text] [PDF]

				A. Daugherty, D. L. Rateri, and H. Lu As Macrophages Indulge, Atherosclerotic Lesions Bulge Circ. Res., June 20, 2008; 102(12): 1445 - 1447. [Full Text] [PDF]

				G. P. Kwon, J. L. Schroeder, M. J. Amar, A. T. Remaley, and R. S. Balaban Contribution of Macromolecular Structure to the Retention of Low-Density Lipoprotein at Arterial Branch Points Circulation, June 3, 2008; 117(22): 2919 - 2927. [Abstract] [Full Text] [PDF]

				M. Pan, V. Maitin, S. Parathath, U. Andreo, S. X. Lin, C. St. Germain, Z. Yao, F. R. Maxfield, K. J. Williams, and E. A. Fisher Presecretory oxidation, aggregation, and autophagic destruction of apoprotein-B: A pathway for late-stage quality control PNAS, April 15, 2008; 105(15): 5862 - 5867. [Abstract] [Full Text] [PDF]

				H. Loppnow, K. Werdan, and M. Buerke Invited review: Vascular cells contribute to atherosclerosis by cytokine- and innate-immunity-related inflammatory mechanisms Innate Immunity, April 1, 2008; 14(2): 63 - 87. [Abstract] [PDF]

				F. Huang, J. C. Thompson, P. G. Wilson, H. H. Aung, J. C. Rutledge, and L. R. Tannock Angiotensin II increases vascular proteoglycan content preceding and contributing to atherosclerosis development J. Lipid Res., March 1, 2008; 49(3): 521 - 530. [Abstract] [Full Text] [PDF]

				K. Jagavelu, U. J.F. Tietge, M. Gaestel, H. Drexler, B. Schieffer, and U. Bavendiek Systemic Deficiency of the MAP Kinase Activated Protein Kinase 2 Reduces Atherosclerosis in Hypercholesterolemic Mice Circ. Res., November 26, 2007; 101(11): 1104 - 1112. [Abstract] [Full Text] [PDF]

				I. Tabas, K. J. Williams, and J. Boren Subendothelial Lipoprotein Retention as the Initiating Process in Atherosclerosis: Update and Therapeutic Implications Circulation, October 16, 2007; 116(16): 1832 - 1844. [Abstract] [Full Text] [PDF]

				M. Gustafsson, M. Levin, K. Skalen, J. Perman, V. Friden, P. Jirholt, S.-O. Olofsson, S. Fazio, M. F. Linton, C. F. Semenkovich, et al. Retention of Low-Density Lipoprotein in Atherosclerotic Lesions of the Mouse: Evidence for a Role of Lipoprotein Lipase Circ. Res., October 12, 2007; 101(8): 777 - 783. [Abstract] [Full Text] [PDF]

				T. Nagao, C. Qin, I. Grosheva, F. R. Maxfield, and L. M. Pierini Elevated Cholesterol Levels in the Plasma Membranes of Macrophages Inhibit Migration by Disrupting RhoA Regulation Arterioscler. Thromb. Vasc. Biol., July 1, 2007; 27(7): 1596 - 1602. [Abstract] [Full Text] [PDF]

				Y. Nakashima, H. Fujii, S. Sumiyoshi, T. N. Wight, and K. Sueishi Early Human Atherosclerosis: Accumulation of Lipid and Proteoglycans in Intimal Thickenings Followed by Macrophage Infiltration Arterioscler. Thromb. Vasc. Biol., May 1, 2007; 27(5): 1159 - 1165. [Abstract] [Full Text] [PDF]

				J. E. Kanter, F. Johansson, R. C. LeBoeuf, and K. E. Bornfeldt Do Glucose and Lipids Exert Independent Effects on Atherosclerotic Lesion Initiation or Progression to Advanced Plaques? Circ. Res., March 30, 2007; 100(6): 769 - 781. [Abstract] [Full Text] [PDF]

				K. Oorni and P. T. Kovanen PLA2-V: A Real Player in Atherogenesis Arterioscler. Thromb. Vasc. Biol., March 1, 2007; 27(3): 445 - 447. [Full Text] [PDF]

				M. Simionescu Implications of Early Structural-Functional Changes in the Endothelium for Vascular Disease Arterioscler. Thromb. Vasc. Biol., February 1, 2007; 27(2): 266 - 274. [Abstract] [Full Text] [PDF]

				M.-L. Liu, M. P. Reilly, P. Casasanto, S. E. McKenzie, and K. J. Williams Cholesterol Enrichment of Human Monocyte/Macrophages Induces Surface Exposure of Phosphatidylserine and the Release of Biologically-Active Tissue Factor-Positive Microvesicles Arterioscler. Thromb. Vasc. Biol., February 1, 2007; 27(2): 430 - 435. [Abstract] [Full Text] [PDF]

				D. M. Schrijvers, G. R.Y. De Meyer, A. G. Herman, and W. Martinet Phagocytosis in atherosclerosis: Molecular mechanisms and implications for plaque progression and stability Cardiovasc Res, February 1, 2007; 73(3): 470 - 480. [Abstract] [Full Text] [PDF]

				A. M. Vaughan and J. F. Oram ABCA1 and ABCG1 or ABCG4 act sequentially to remove cellular cholesterol and generate cholesterol-rich HDL J. Lipid Res., November 1, 2006; 47(11): 2433 - 2443. [Abstract] [Full Text] [PDF]

				M. Rahmani, R. P. Cruz, D. J. Granville, and B. M. McManus Allograft Vasculopathy Versus Atherosclerosis Circ. Res., October 13, 2006; 99(8): 801 - 815. [Abstract] [Full Text] [PDF]

				L. A. Cuniberti, P. G. Stutzbach, E. Guevara, G. G. Yannarelli, R. P. Laguens, and R. R. Favaloro Development of Mild Aortic Valve Stenosis in a Rabbit Model of Hypertension J. Am. Coll. Cardiol., June 6, 2006; 47(11): 2303 - 2309. [Abstract] [Full Text] [PDF]

				J. Dong, J. Liu, B. Lou, Z. Li, X. Ye, M. Wu, and X.-C. Jiang Adenovirus-mediated overexpression of sphingomyelin synthases 1 and 2 increases the atherogenic potential in mice J. Lipid Res., June 1, 2006; 47(6): 1307 - 1314. [Abstract] [Full Text] [PDF]

				K. J. Williams and I. Tabas Letter by Williams and Tabas Regarding Article "Atherosclerosis 2005: Recent Discoveries and Novel Hypotheses" Circulation, May 30, 2006; 113(21): e782 - e782. [Full Text] [PDF]

				J. Nigro, N. Osman, A. M. Dart, and P. J. Little Insulin Resistance and Atherosclerosis Endocr. Rev., May 1, 2006; 27(3): 242 - 259. [Abstract] [Full Text] [PDF]

				L. M. Wilson, C. L. L. Pham, A. J. Jenkins, J. D. Wade, A. F. Hill, M. A. Perugini, and G. J. Howlett High density lipoproteins bind A{beta} and apolipoprotein C-II amyloid fibrils J. Lipid Res., April 1, 2006; 47(4): 755 - 760. [Abstract] [Full Text] [PDF]

				M. Y. Chang, C.-Y. Han, T. N. Wight, and A. Chait Antioxidants Inhibit the Ability of Lysophosphatidylcholine to Regulate Proteoglycan Synthesis Arterioscler. Thromb. Vasc. Biol., March 1, 2006; 26(3): 494 - 500. [Abstract] [Full Text] [PDF]

				R. Oksjoki, P. T. Kovanen, K. A. Lindstedt, B. Jansson, and M. O. Pentikainen OxLDL-IgG Immune Complexes Induce Survival of Human Monocytes Arterioscler. Thromb. Vasc. Biol., March 1, 2006; 26(3): 576 - 583. [Abstract] [Full Text] [PDF]

				L. D. Adams, R. L. Geary, J. Li, A. Rossini, and S. M. Schwartz Expression Profiling Identifies Smooth Muscle Cell Diversity Within Human Intima and Plaque Fibrous Cap: Loss of RGS5 Distinguishes the Cap Arterioscler. Thromb. Vasc. Biol., February 1, 2006; 26(2): 319 - 325. [Abstract] [Full Text] [PDF]

				C. Qin, T. Nagao, I. Grosheva, F. R. Maxfield, and L. M. Pierini Elevated Plasma Membrane Cholesterol Content Alters Macrophage Signaling and Function Arterioscler. Thromb. Vasc. Biol., February 1, 2006; 26(2): 372 - 378. [Abstract] [Full Text] [PDF]

				M. Rodriguez-Lee, G. Ostergren-Lunden, B. Wallin, J. Moses, G. Bondjers, and G. Camejo Fatty Acids Cause Alterations of Human Arterial Smooth Muscle Cell Proteoglycans That Increase the Affinity for Low-Density Lipoprotein Arterioscler. Thromb. Vasc. Biol., January 1, 2006; 26(1): 130 - 135. [Abstract] [Full Text] [PDF]

				C. Edelstein, M. Yousef, and A. M. Scanu Elements in the C terminus of apolipoprotein [a] responsible for the binding to the tenth type III module of human fibronectin J. Lipid Res., December 1, 2005; 46(12): 2673 - 2680. [Abstract] [Full Text] [PDF]

				M. Sneck, P. T. Kovanen, and K. Oorni Decrease in pH Strongly Enhances Binding of Native, Proteolyzed, Lipolyzed, and Oxidized Low Density Lipoprotein Particles to Human Aortic Proteoglycans J. Biol. Chem., November 11, 2005; 280(45): 37449 - 37454. [Abstract] [Full Text] [PDF]

				I. Tabas Consequences and Therapeutic Implications of Macrophage Apoptosis in Atherosclerosis: The Importance of Lesion Stage and Phagocytic Efficiency Arterioscler. Thromb. Vasc. Biol., November 1, 2005; 25(11): 2255 - 2264. [Abstract] [Full Text] [PDF]

				B. B. Boyanovsky, D. R. van der Westhuyzen, and N. R. Webb Group V Secretory Phospholipase A2-modified Low Density Lipoprotein Promotes Foam Cell Formation by a SR-A- and CD36-independent Process That Involves Cellular Proteoglycans J. Biol. Chem., September 23, 2005; 280(38): 32746 - 32752. [Abstract] [Full Text] [PDF]

				V. Fuster, P. R. Moreno, Z. A. Fayad, R. Corti, and J. J. Badimon Atherothrombosis and High-Risk Plaque: Part I: Evolving Concepts J. Am. Coll. Cardiol., September 20, 2005; 46(6): 937 - 954. [Abstract] [Full Text] [PDF]

				A. Daugherty, N. R. Webb, D. L. Rateri, and V. L. King Thematic review series: The Immune System and Atherogenesis. Cytokine regulation of macrophage functions in atherogenesis J. Lipid Res., September 1, 2005; 46(9): 1812 - 1822. [Abstract] [Full Text] [PDF]

				X. Zeng, J. Chen, Y. I. Miller, K. Javaherian, and K. S. Moulton Endostatin binds biglycan and LDL and interferes with LDL retention to the subendothelial matrix during atherosclerosis J. Lipid Res., September 1, 2005; 46(9): 1849 - 1859. [Abstract] [Full Text] [PDF]

				P. Davidsson, J. Hulthe, B. Fagerberg, B.-M. Olsson, C. Hallberg, B. Dahllof, and G. Camejo A proteomic study of the apolipoproteins in LDL subclasses in patients with the metabolic syndrome and type 2 diabetes J. Lipid Res., September 1, 2005; 46(9): 1999 - 2006. [Abstract] [Full Text] [PDF]

				P. Talusan, S. Bedri, S. Yang, T. Kattapuram, N. Silva, P. J. Roughley, and J. R. Stone Analysis of Intimal Proteoglycans in Atherosclerosis-prone and Atherosclerosis-resistant Human Arteries by Mass Spectrometry Mol. Cell. Proteomics, September 1, 2005; 4(9): 1350 - 1357. [Abstract] [Full Text] [PDF]

				J. Tian, K. Ishibashi, K. Ishibashi, K. Reiser, R. Grebe, S. Biswal, P. Gehlbach, and J. T. Handa Advanced glycation endproduct-induced aging of the retinal pigment epithelium and choroid: A comprehensive transcriptional response PNAS, August 16, 2005; 102(33): 11846 - 11851. [Abstract] [Full Text] [PDF]

				K. J. Williams and I. Tabas Lipoprotein Retention--and Clues for Atheroma Regression Arterioscler. Thromb. Vasc. Biol., August 1, 2005; 25(8): 1536 - 1540. [Abstract] [Full Text] [PDF]

				K. Oorni, P. Posio, M. Ala-Korpela, M. Jauhiainen, and P. T. Kovanen Sphingomyelinase Induces Aggregation and Fusion of Small Very Low-Density Lipoprotein and Intermediate-Density Lipoprotein Particles and Increases Their Retention to Human Arterial Proteoglycans Arterioscler. Thromb. Vasc. Biol., August 1, 2005; 25(8): 1678 - 1683. [Abstract] [Full Text] [PDF]

				K. Reifenberg, H.-A. Lehr, D. Baskal, E. Wiese, S. C. Schaefer, S. Black, D. Samols, M. Torzewski, K. J. Lackner, M. Husmann, et al. Role of C-Reactive Protein in Atherogenesis: Can the Apolipoprotein E Knockout Mouse Provide the Answer? Arterioscler. Thromb. Vasc. Biol., August 1, 2005; 25(8): 1641 - 1646. [Abstract] [Full Text] [PDF]

				C.-M. Li, B. H. Chung, J. B. Presley, G. Malek, X. Zhang, N. Dashti, L. Li, J. Chen, K. Bradley, H. S. Kruth, et al. Lipoprotein-like Particles and Cholesteryl Esters in Human Bruch's Membrane: Initial Characterization Invest. Ophthalmol. Vis. Sci., July 1, 2005; 46(7): 2576 - 2586. [Abstract] [Full Text] [PDF]

				C.-M. Li, J. B. Presley, X. Zhang, N. Dashti, B. H. Chung, N. E. Medeiros, C. Guidry, and C. A. Curcio Retina expresses microsomal triglyceride transfer protein: implications for age-related maculopathy J. Lipid Res., April 1, 2005; 46(4): 628 - 640. [Abstract] [Full Text] [PDF]

				K. Hashimura, K. Sudhir, J. Nigro, S. Ling, M. R. I. Williams, P. A. Komesaroff, and P. J. Little Androgens Stimulate Human Vascular Smooth Muscle Cell Proteoglycan Biosynthesis and Increase Lipoprotein Binding Endocrinology, April 1, 2005; 146(4): 2085 - 2090. [Abstract] [Full Text] [PDF]

				K. D. O'Brien, T. O. McDonald, V. Kunjathoor, K. Eng, E. A. Knopp, K. Lewis, R. Lopez, E. A. Kirk, A. Chait, T. N. Wight, et al. Serum Amyloid A and Lipoprotein Retention in Murine Models of Atherosclerosis Arterioscler. Thromb. Vasc. Biol., April 1, 2005; 25(4): 785 - 790. [Abstract] [Full Text] [PDF]

				M. Rahmani, J. T. Read, J. M. Carthy, P. C. McDonald, B. W. Wong, M. Esfandiarei, X. Si, Z. Luo, H. Luo, P. S. Rennie, et al. Regulation of the Versican Promoter by the {beta}-Catenin-T-cell Factor Complex in Vascular Smooth Muscle Cells J. Biol. Chem., April 1, 2005; 280(13): 13019 - 13028. [Abstract] [Full Text] [PDF]

				A. Chait, C. Y. Han, J. F. Oram, and J. W. Heinecke Thematic review series: The Immune System and Atherogenesis. Lipoprotein-associated inflammatory proteins: markers or mediators of cardiovascular disease? J. Lipid Res., March 1, 2005; 46(3): 389 - 403. [Abstract] [Full Text] [PDF]

				S. A. I. Ghesquiere, M. J. J. Gijbels, M. Anthonsen, P. J. J. van Gorp, I. van der Made, B. Johansen, M. H. Hofker, and M. P. J. de Winther Macrophage-specific overexpression of group IIa sPLA2 increases atherosclerosis and enhances collagen deposition J. Lipid Res., February 1, 2005; 46(2): 201 - 210. [Abstract] [Full Text] [PDF]

				M. B. Kahn, K. Boesze-Battaglia, D. W. Stepp, A. Petrov, Y. Huang, R. P. Mason, and T. N. Tulenko Influence of serum cholesterol on atherogenesis and intimal hyperplasia after angioplasty: inhibition by amlodipine Am J Physiol Heart Circ Physiol, February 1, 2005; 288(2): H591 - H600. [Abstract] [Full Text] [PDF]

				Z. Zhao, M. C. de Beer, L. Cai, R. Asmis, F. C. de Beer, W. J.S. de Villiers, and D. R. van der Westhuyzen Low-Density Lipoprotein From Apolipoprotein E-Deficient Mice Induces Macrophage Lipid Accumulation in a CD36 and Scavenger Receptor Class A-Dependent Manner Arterioscler. Thromb. Vasc. Biol., January 1, 2005; 25(1): 168 - 173. [Abstract] [Full Text] [PDF]

				M. F. Khalil, W. D. Wagner, and I. J. Goldberg Molecular Interactions Leading to Lipoprotein Retention and the Initiation of Atherosclerosis Arterioscler. Thromb. Vasc. Biol., December 1, 2004; 24(12): 2211 - 2218. [Abstract] [Full Text] [PDF]

				T.-S. Park, R. L. Panek, S. B. Mueller, J. C. Hanselman, W. S. Rosebury, A. W. Robertson, E. K. Kindt, R. Homan, S. K. Karathanasis, and M. D. Rekhter Inhibition of Sphingomyelin Synthesis Reduces Atherogenesis in Apolipoprotein E-Knockout Mice Circulation, November 30, 2004; 110(22): 3465 - 3471. [Abstract] [Full Text] [PDF]

				C. Verseyden, S. Meijssen, and M. C. Cabezas Effects of Atorvastatin on Fasting Plasma and Marginated Apolipoproteins B48 and B100 in Large, Triglyceride-Rich Lipoproteins in Familial Combined Hyperlipidemia J. Clin. Endocrinol. Metab., October 1, 2004; 89(10): 5021 - 5029. [Abstract] [Full Text] [PDF]

				R. Stocker and J. F. Keaney Jr. Role of Oxidative Modifications in Atherosclerosis Physiol Rev, October 1, 2004; 84(4): 1381 - 1478. [Abstract] [Full Text] [PDF]

				R. K. Vikramadithyan, Y. Kako, G. Chen, Y. Hu, E. Arikawa-Hirasawa, Y. Yamada, and I. J. Goldberg Atherosclerosis in perlecan heterozygous mice J. Lipid Res., October 1, 2004; 45(10): 1806 - 1812. [Abstract] [Full Text] [PDF]

				K. Oorni, M. Sneck, D. Bromme, M. O. Pentikainen, K. A. Lindstedt, M. Mayranpaa, H. Aitio, and P. T. Kovanen Cysteine Protease Cathepsin F Is Expressed in Human Atherosclerotic Lesions, Is Secreted by Cultured Macrophages, and Modifies Low Density Lipoprotein Particles in Vitro J. Biol. Chem., August 13, 2004; 279(33): 34776 - 34784. [Abstract] [Full Text] [PDF]

				K. E. Lewis, E. A. Kirk, T. O. McDonald, S. Wang, T. N. Wight, K. D. O'Brien, and A. Chait Increase in Serum Amyloid A Evoked by Dietary Cholesterol Is Associated With Increased Atherosclerosis in Mice Circulation, August 3, 2004; 110(5): 540 - 545. [Abstract] [Full Text] [PDF]

				T. N. Wight and M. J. Merrilees Proteoglycans in Atherosclerosis and Restenosis: Key Roles for Versican Circ. Res., May 14, 2004; 94(9): 1158 - 1167. [Abstract] [Full Text] [PDF]

				A. E. Cozen, H. Moriwaki, M. Kremen, M. B. DeYoung, H. L. Dichek, K. I. Slezicki, S. G. Young, M. Veniant, and D. A. Dichek Macrophage-Targeted Overexpression of Urokinase Causes Accelerated Atherosclerosis, Coronary Artery Occlusions, and Premature Death Circulation, May 4, 2004; 109(17): 2129 - 2135. [Abstract] [Full Text] [PDF]

				C. Flood, M. Gustafsson, R. E. Pitas, L. Arnaboldi, R. L. Walzem, and J. Boren Molecular Mechanism for Changes in Proteoglycan Binding on Compositional Changes of the Core and the Surface of Low-Density Lipoprotein-Containing Human Apolipoprotein B100 Arterioscler. Thromb. Vasc. Biol., March 1, 2004; 24(3): 564 - 570. [Abstract] [Full Text]

				E. F LaBelle and T. N Tulenko LDL, IGF-1, and VSMC apoptosis: linking atherogenesis to plaque rupture in vulnerable lesions Cardiovasc Res, February 1, 2004; 61(2): 204 - 205. [Full Text] [PDF]

				M. Formato, M. Farina, R. Spirito, M. Maggioni, A. Guarino, G. M. Cherchi, P. Biglioli, C. Edelstein, and A. M. Scanu Evidence for a Proinflammatory and Proteolytic Environment in Plaques From Endarterectomy Segments of Human Carotid Arteries Arterioscler. Thromb. Vasc. Biol., January 1, 2004; 24(1): 129 - 135. [Abstract] [Full Text] [PDF]

				X.-C. Jiang, T. P. Beyer, Z. Li, J. Liu, W. Quan, R. J. Schmidt, Y. Zhang, W. R. Bensch, P. I. Eacho, and G. Cao Enlargement of High Density Lipoprotein in Mice via Liver X Receptor Activation Requires Apolipoprotein E and Is Abolished by Cholesteryl Ester Transfer Protein Expression J. Biol. Chem., December 5, 2003; 278(49): 49072 - 49078. [Abstract] [Full Text] [PDF]

				F. E. Thorngate, P. G. Yancey, G. Kellner-Weibel, L. L. Rudel, G. H. Rothblat, and D. L. Williams Testing the role of apoA-I, HDL, and cholesterol efflux in the atheroprotective action of low-level apoE expression J. Lipid Res., December 1, 2003; 44(12): 2331 - 2338. [Abstract] [Full Text] [PDF]

				M. Patel, J. Morrow, F. R. Maxfield, D. K. Strickland, S. Greenberg, and I. Tabas The Cytoplasmic Domain of the Low Density Lipoprotein (LDL) Receptor-related Protein, but Not That of the LDL Receptor, Triggers Phagocytosis J. Biol. Chem., November 7, 2003; 278(45): 44799 - 44807. [Abstract] [Full Text] [PDF]

				C. D. Meyers, L. R. Tannock, T. N. Wight, and A. Chait Statin-exposed vascular smooth muscle cells secrete proteoglycans with decreased binding affinity for LDL J. Lipid Res., November 1, 2003; 44(11): 2152 - 2160. [Abstract] [Full Text] [PDF]

				W. Cao, Y. V Bobryshev, R. S.A Lord, R. E.I Oakley, S. H Lee, and J. Lu Dendritic cells in the arterial wall express C1q: potential significance in atherogenesis Cardiovasc Res, October 15, 2003; 60(1): 175 - 186. [Abstract] [Full Text] [PDF]

				B. OSTERUD and E. BJORKLID Role of Monocytes in Atherogenesis Physiol Rev, October 1, 2003; 83(4): 1069 - 1112. [Abstract] [Full Text] [PDF]

				G McGwin Jr, C Owsley, C A Curcio, and R J Crain The association between statin use and age related maculopathy Br. J. Ophthalmol., September 1, 2003; 87(9): 1121 - 1125. [Abstract] [Full Text] [PDF]

				G. Camejo Hydrolytic Enzymes Released From Resident Macrophages and Located in the Intima Extracellular Matrix as Agents That Modify Retained Apolipoprotein B Lipoproteins Arterioscler. Thromb. Vasc. Biol., August 1, 2003; 23(8): 1312 - 1313. [Full Text] [PDF]

				T. B. Twickler, M. J. M. Cramer, G. M. Dallinga-Thie, M. J. Chapman, D. W. Erkelens, and H. P. F. Koppeschaar Adult-Onset Growth Hormone Deficiency: Relation of Postprandial Dyslipidemia to Premature Atherosclerosis J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2479 - 2488. [Full Text] [PDF]

				M. Y. Chang, C. Tsoi, T. N. Wight, and A. Chait Lysophosphatidylcholine Regulates Synthesis of Biglycan and the Proteoglycan Form of Macrophage Colony Stimulating Factor Arterioscler. Thromb. Vasc. Biol., May 1, 2003; 23(5): 809 - 815. [Abstract] [Full Text] [PDF]

				Z. Chen, R. L. Fitzgerald, J. E. Saffitz, C. F. Semenkovich, and G. Schonfeld Amino Terminal 38.9% of Apolipoprotein B-100 Is Sufficient to Support Cholesterol-Rich Lipoprotein Production and Atherosclerosis Arterioscler. Thromb. Vasc. Biol., April 1, 2003; 23(4): 668 - 674. [Abstract] [Full Text] [PDF]

				T. Nassar, B. S. Sachais, S.'e. Akkawi, M. A. Kowalska, K. Bdeir, E. Leitersdorf, E. Hiss, L. Ziporen, M. Aviram, D. Cines, et al. Platelet Factor 4 Enhances the Binding of Oxidized Low-density Lipoprotein to Vascular Wall Cells J. Biol. Chem., February 14, 2003; 278(8): 6187 - 6193. [Abstract] [Full Text] [PDF]

				G. Malek, C.-M. Li, C. Guidry, N. E. Medeiros, and C. A. Curcio Apolipoprotein B in Cholesterol-Containing Drusen and Basal Deposits of Human Eyes with Age-Related Maculopathy Am. J. Pathol., February 1, 2003; 162(2): 413 - 425. [Abstract] [Full Text] [PDF]

				K. Olin-Lewis, R. M. Krauss, M. La Belle, P. J. Blanche, P. H. R. Barrett, T. N. Wight, and A. Chait ApoC-III content of apoB-containing lipoproteins is associated with binding to the vascular proteoglycan biglycan J. Lipid Res., November 1, 2002; 43(11): 1969 - 1977. [Abstract] [Full Text] [PDF]

				A. Zalewski, Y. Shi, and A. G. Johnson Diverse Origin of Intimal Cells: Smooth Muscle Cells, Myofibroblasts, Fibroblasts, and Beyond? Circ. Res., October 18, 2002; 91(8): 652 - 655. [Full Text] [PDF]

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