© 1996 American Heart Association, Inc.
Articles |
Development of the Lipid-Rich Core in Human Atherosclerosis
From the Departments of Medicine and Pathology, The Sarah W. Stedman Center for Nutritional Studies, Duke University Medical Center, Durham, NC.
Key Words: atherosclerosis • lipid core • fibrous plaque • cholesterol
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Introduction |
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 Top Introduction Core Initiation Is an...Both Free and Esterified...Lipoprotein Aggregation and...Formation of Cholesterol-Rich...Core Lipids Are Partially...Some Proteins Accumulate...Lipid and Protein Components...Summary References |
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The core region of atherosclerotic plaques is characterized by profuse lipid deposition and disappearance of cells and fibrous tissue elements. Enlargement of the core, unless impeded or contained, leads to plaque rupture and consequently arterial thrombosis.1 2 3 Although the core has been examined most commonly in advanced atherosclerosis, recent studies have shown that it originates early in lesion development—at the stage of transition from fatty streak to fibrous plaque.4 5 Thus, the development of the atherosclerotic core spans the entire period of fibrous plaque evolution, emphasizing the need to understand the cellular and extracellular processes that underlie core development.
This is the first review to focus specifically on the origins and characteristics of the abundant extracellular lipid deposits and associated proteins found in the atherosclerotic core. A complete understanding of core development must include topics such as cytotoxicity, calcification, neovascularization, matrix degradation, and plaque rupture, but space permits only minimal coverage here, and the reader is referred to other articles and reviews.2 3 6 7 8 9 10 11 12 13 14
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Core Initiation Is an Early Event in Lesion Development |
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TopIntroductionCore Initiation Is an...Both Free and Esterified...Lipoprotein Aggregation and...Formation of Cholesterol-Rich...Core Lipids Are Partially...Some Proteins Accumulate...Lipid and Protein Components...Summary References |
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Core initiation may be recognized by the onset of typical lipid deposits, the partial disappearance of cells, or both. Early manifestations are difficult to discern in routine, paraffin-embedded tissue, primarily because of solvent extraction of the characteristic lipid deposits. Nevertheless, Restrepo and Tracy15 noted foci of necrosis in human aortic fatty streaks and associated the presence of such foci with the subsequent development of fibrous plaques. Katz et al16 examined tissue minces of arterial intima without solvents and found cholesterol crystals in a subset of flat human aortic lesions with the surface appearance of fatty streaks. The lesions that contained cholesterol crystals also showed relatively high levels of free cholesterol by chemical analysis.
Epoxy-embedded tissue affords greatly improved recognition of the tissue clefts vacated by solvent extraction of small cholesterol crystals. Using this approach, we examined flat human aortic fatty lesions similar to those described by Katz and colleagues.16 Cholesterol clefts were found in approximately one fifth of such "fatty streaks" obtained from young adults. In the musculoelastic (deep) intimal sublayer, where the clefts appeared, a significant decrease in overall cell volume was determined by morphometry. The combination of cholesterol clefts and cell disappearance was interpreted as showing the origin of the atherosclerotic core.4
A previous study of small, raised, lipid-containing lesions
found in aortas from young adults also suggested an early appearance of
the core in human atherogenesis. In almost every lesion, the lipid
appeared in two locations: superficial intimal foam cells and a deep
intimal core (Fig 1
). Partial disappearance of cells
from the core was demonstrated. These small, raised lesions, termed
"fibrolipid lesions," were in essence small fibrous plaques. The
core was already well developed in many lesions at a very early stage
of fibrous plaque development.17 18 Chemical
analysis revealed that the early atherosclerotic core in these
lesions had a remarkably high content of free cholesterol,
averaging 63% of total cholesterol.19 This
was surprising because the presumed sources of lipid for the early core
were either foam cells or tissue lipoproteins, both of which are rich
in esterified cholesterol compared with free
cholesterol. Nevertheless, the findings were
consistent with the earlier work of Katz et al16
as well as our study of grossly identified fatty
streaks.4
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The findings in human aorta demonstrated a sequence of lesion transition from fatty streaks to fibrous plaques. A similar transitional sequence was demonstrated by Stary et al5 20 in human coronary arteries. Notably, the type III or intermediate lesion from Stary's work and a consensus article is characterized by the development of "extracellular lipid particles [forming] pool-like aggregates in the musculoelastic layer," a description consistent with the results described above.
The new findings suggest that our understanding of overall lesion development should be modified, because initiation of the lesion core occurs much earlier than previously supposed. In particular, the focal intimal growth characteristic of fibrous plaques, comprising both cell proliferation and matrix synthesis, may commonly occur after the onset of significant cellular stress in the deep intima, as evidenced by loss of cells from this region. Furthermore, the role of excessive free cholesterol in both cellular toxicity and intimal growth should be considered. We will return to the role of free cholesterol later in this review.
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Both Free and Esterified Cholesterol Accumulate in Extracellular Locations |
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The cores of larger human atherosclerotic fibrous plaques are completely or almost completely acellular, and thus the lipid deposits are almost entirely extracellular. Where does the extracellular lipid come from? The simplest proposal is that it represents the debris of dead foam cells. Part of the appeal of this proposal is that a great deal has been learned about the mechanisms of foam cell lipid accumulation. However, the origin of the extracellular deposits must be considered on the basis of evidence pertaining specifically to them.
The extracellular lipid deposits fall into two major categories. Most
areas within the core region exhibit a predominance of either
cholesterol-rich vesicles, associated with
cholesterol crystals, or cholesteryl ester–rich oily
droplets, typically without crystals.21 The
heterogeneity of core lipids is shown in Figs 2 and
3. As mentioned above, the early core has
shown thus far only the first pattern comprising vesicular/crystalline
deposits rich in free cholesterol.19
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The hypothesis of foam cell death, as an uncomplicated process, cannot account for extracellular lipid deposits rich in free cholesterol, because foam cells contain predominantly esterified cholesterol. Moreover, it is also doubtful that foam cell death accounts for most of the cholesteryl ester found in the core. An observation first made by Smith22 some 20 years ago and verified repeatedly is that the fatty acids esterified to cholesterol in the core consist in large part of linoleate, similar to plasma lipoproteins and dissimilar from the oleate predominance of cholesteryl ester fatty acids resulting from lipid processing in lesion foam cells. The discrepancy in cholesteryl ester fatty acyl patterns has been confirmed in comparisons of foam cell–rich areas versus core areas within the same microdissected lesions.19 23 These results suggest that cholesteryl esters in the atherosclerotic core are derived more or less directly from tissue lipoproteins, without intervening steps of uptake and processing in cells. More recently, a marked difference in the sizes of extracellular lipid droplets and foam cell lipid droplets was noted. In the core of mature fibrous plaques, approximately 90% of the area of extracellular oily droplets appeared in droplets much smaller than typical foam cell lipid droplets.21 Extracellular lipid droplets large enough to suggest simple derivation from foam cells were uncommon. It is also pertinent to note that in both atherosclerotic and normal human arterial intima, lipid droplets can be found abundantly within the seams of elastic fibers in the deep intima, an ultrastructural location that seems to exclude foam cell derivation.24
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Lipoprotein Aggregation and Fusion Is a Mechanism for Extracellular Lipid Accumulation |
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Besides foam cell death, what other mechanisms can account for the formation of extracellular lipid deposits? A new hypothesis states that lipoproteins, particularly LDL, aggregate and then fuse with each other in the extracellular space to form microscopically evident lipid deposits.25 26 27 28 29 30 31 32 33 Structures resembling lipoprotein aggregates have been visualized in human arterial intima by electron microscopy,4 24 and lipid aggregates containing apolipoprotein B (apoB) and having ultracentrifugal density similar to LDL have been isolated.29 34 35 LDL aggregation can be induced in vitro by a wide variety of physical and biochemical agents (Table 1
). Khoo and colleagues36 found that
vortex-induced aggregation of LDL was strongly inhibited in the
presence of HDL or apoA-I. After vortexing or mast cell granule
protease treatment of LDL, fusion of the aggregated particles has been
demonstrated by electron microscopy.26 27 When LDL
particles fuse, physical redistribution of amphiphilic and oily lipids
must occur, resulting in the formation of both vesicles and oily
droplets. Lipid structures formed after vortexing of LDL were
ultrastructurally similar to those found in the core of human
atherosclerotic plaques.27
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The hyperlipidemic rabbit between the first and second weeks after the onset of cholesterol feeding provides a valuable model of extracellular arterial lipid deposition. At this time, before the migration of monocytes into the subendothelial space, deposition of extracellular lipid can be found beneath the endothelium near branch orifices in the aortic arch.45 46 47 Using freeze-etch electron microscopy, Frank and Fogelman26 examined this area in both cholesterol-fed and Watanabe heritable hyperlipidemic rabbits. The aortic subendothelium contained aggregates of round particles of the same size as the plasma lipoproteins, in the midst of which larger round particles also appeared, suggesting lipoprotein fusion. In subsequent studies, human LDL was injected intravenously into previously normocholesterolemic rabbits to achieve high circulating levels. After only 2 hours, aggregates of LDL-sized and larger particles appeared in the subendothelial space, again suggesting fusion.48 Similar results were obtained when LDL was applied in vitro to excised rabbit cardiac valves.49
A conceptual point stems from consideration of the irreversibility of many types of lipoprotein aggregation. Aggregation of LDL was initially described as a modification that would cause foam cell formation from macrophages.25 Often, the formation of lipid deposits in foam cells is depicted as the key process that immobilizes lipid in lesions. To the extent that aggregation and fusion of lipoproteins is irreversible, however, the lipid is thereby immobilized in the extracellular space and thus already represents tissue lipid accumulation. Subsequent uptake into cells alters the form of the lipid but does not represent further accumulation. Indeed, a hypothesis can be posed for future research that cellular uptake of aggregated LDL might represent a key step in lipid removal from arterial tissue.
To summarize, compelling evidence suggests that lipoprotein aggregation/fusion is an extracellular pathway for lipid deposition in atherosclerosis. However, the magnitude of its effect and the factors that might influence it are just beginning to be understood.32 33 36
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Formation of Cholesterol-Rich Vesicles Is an Unsolved Problem |
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Vesicles rich in free cholesterol were recognized as distinct lipid deposits in atherosclerosis by Kruth50 and Chao and colleagues,51 52 53 who first identified them by staining with filipin and subsequently isolated them from human and rabbit arterial intima. Table 2
is
a list of potential mechanisms by which
cholesterol-rich vesicles might be formed during
atherogenesis. Assuming that the source of the cholesterol
is plasma lipoproteins, each proposed mechanism must attempt to explain
why entire areas within the lesion can become enriched in free
cholesterol and relatively depleted of esterified
cholesterol compared with lipoproteins. Thus, lipoprotein
aggregation and fusion, which produce both cholesteryl ester droplets
and cholesterol-rich vesicles, cannot fully explain the
formation of an atherosclerotic core that contains predominantly
vesicles. This will be a viable explanation only if an additional
mechanism for removal or hydrolysis of the cholesteryl ester can be
defined.
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Experimental models for the formation of cholesterol-rich vesicles are beginning to emerge. The animal model mentioned above, rabbits examined 1 to 2 weeks after the onset of cholesterol feeding, shows mostly vesicular, cholesterol-rich lipid deposits beneath the arterial endothelium.45 46 47 Further study of the chemistry and ultrastructure of this process may provide insight into mechanisms of formation of the vesicles. Mitchinson and colleagues54 have proposed that many of the vesicles in human atherosclerosis represent ceroid, a peroxidized and cross-linked complex of lipid and protein. Ceroid can be generated in vitro by macrophages exposed to LDL or to polyunsaturated cholesteryl esters. There is no doubt that ceroid is found in the core region of plaques, but quantitative assessment is needed. An early estimate suggested that it may account for only 1% to 5% of the core lipids,55 rather than the approximate 25% area fraction occupied by vesicles.21
Experiments by Tangirala and coworkers56 have examined the mechanisms by which lysosomal hydrolysis of cholesteryl ester can contribute to the accumulation of free cholesterol in cultured cells. When macrophages were loaded rapidly with cholesteryl ester by phagocytosis of preformed large lipid droplets, substantial amounts of free cholesterol accumulated in lysosomes via hydrolysis, and this accumulation was exacerbated by inefficient transfer of cholesterol to extralysosomal locations. Further incubation of the cells after loading led to the formation of cholesterol crystals within the lysosomes. Extracellular crystals also appeared in the culture medium at extended time points.57 Cultured vascular smooth muscle cells also took up lipid droplets into lysosomes by phagocytosis, but these cells accumulated excess free cholesterol in a compartment identical to or closely linked with the plasma membrane, suggesting inefficient cytoplasmic reesterification.58 The findings with smooth muscle cells are of additional interest because initiation of the cholesterol-rich core in human atherosclerosis has been localized to the musculoelastic (deep) intimal sublayer, where the cell type is predominantly smooth muscle in early lesions.4 19
How might cellular accumulation of free cholesterol lead to formation of the extracellular cholesterol-rich vesicles found in lesions? Some of the possible mechanisms are selective or nonselective cell death, detachment of cellular blebs, or extrusion of lysosomal contents. Schmitz, Robenek, and colleagues59 60 reported a model that supports the last of these hypotheses. Macrophages first were loaded with lysosomal lipid by a brief treatment with acetylated LDL and then were incubated with nifedipine in lipoprotein-free medium. During nifedipine treatment, cholesterol-rich lamellar bodies were released from lysosomes into the medium.
Finally, Chung and colleagues61 proposed a novel mechanism whereby the vesicles are formed extracellularly, not from LDL as commonly assumed but from an interaction of VLDL, HDL, and lipoprotein lipase. In support of their proposal, cholesterol-rich vesicles from human aorta were found to contain apoA-I and several apoC species but only scant apoB.
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Core Lipids Are Partially Oxidized |
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Oxidized derivatives of cholesterol and cholesteryl esters were first identified in human atherosclerosis by Brooks et al.62 Subsequently, oxidized LDL was found within human lesions.63 Myeloperoxidase, an oxidative enzyme produced by monocytes and granulocytes, was found in both the shoulder regions and the core of fibrous plaques.64 Interestingly, oxidation of LDL can promote aggregation, linking these two processes.33
Recently, Carpenter and colleagues65 measured oxidized lipids found in the core ("necrotic gruel") of advanced human aortic plaques. Hydroperoxy- and hydroxyoctadecadienoic acids, which are derived from linoleic acid by lipid peroxidation, were present at levels totaling 6% to 7% of that of linoleic acid measured in the same material. These percentages fall within the range recorded for copper-oxidized LDL.66 Carpenter et al also quantified 7ß-OH-cholesterol after saponification and sodium borohydride reduction of core lipids. The resulting 7ß-OH-cholesterol concentration, representing most of the oxysterols formed via lipid peroxidation from cholesterol, was only 0.14% of total cholesterol, far less than the relative concentration of oxysterols formed in most in vitro models of lipoprotein oxidation. An enzymatically oxidized derivative of cholesterol, 26-OH-cholesterol, was approximately fivefold more abundant in core lipids than 7ß-OH-cholesterol. The 7ß-hydroperoxide of cholesterol may have considerably greater bioactivity than the corresponding hydroxy and keto derivatives. The hydroperoxide was recently identified in human plaques by Chisolm and colleagues.8 Thus, significant evidence of lipid oxidation has been found in the atherosclerotic core, although the formation or retention of oxysterols appears to be less than that obtained with oxidation of lipoproteins in vitro.
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Some Proteins Accumulate Selectively in the Atherosclerotic Core |
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A number of proteins and peptides have been detected in relative abundance within or near the atherosclerotic core (Table 3
).
Interpretation of results can be complicated,
especially when paraffin sections are used. Unless large
cholesterol clefts are evident, the acellular or
hypocellular lipid-rich core can sometimes be difficult to
distinguish from a hypocellular, lipid-poor region of fibrous
tissue. Connective tissue stains of paraffin sections or lipid
histochemical procedures on frozen sections are helpful. Antigenicity
of peptides such as apolipoproteins is often decreased at the center of
the core, owing perhaps to oxidation, proteolysis, and age of the
deposits. The molecular associations of some antigens can be altered.
In atherosclerotic plaques with large cores, treatment with Triton
X-100 was necessary to extract most of the immunoassayable
apoB.82
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As might be expected, many of the proteins found in the core are relatively hydrophobic, including the apolipoproteins, C-reactive protein (a plasma acute phase reactant), and the 70- and 60-kD heat-shock proteins. Since heat-shock proteins are upregulated during periods of cell stress, they may reflect toxic effects of core lipids (perhaps oxidized lipids) on cells in the surrounding tissue. Abundant deposits of fibrinogen have been found in atherosclerotic lesions; this protein was sometimes but not always associated with the core.70 71 72 Digestion of lesion tissue with plasmin, which degrades fibrinogen, released large amounts of previously bound apoB.83 This observation suggested a role for fibrinogen in the immobilization of LDL in lesions. However, further work is needed because plasmin is a relatively nonspecific protease.
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Lipid and Protein Components of the Core May Lead to Cellular Responses |
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Cells that border and penetrate the atherosclerotic core not only may participate in the deposition (or removal) of core lipids but may also be influenced by the accumulating lipids and proteins. Complement components have been found in relative abundance in the core, and both toxic and chemotactic responses may be generated via activation of complement on core lipids.76 Antigenic markers of complement activation, including C3d and the terminal C5b-9 neoantigen, were found in the atherosclerotic core, and terminal C5b-9 was also found coincident with cholesterol-rich vesicles in the subendothelium of cholesterol-fed rabbits.77 84 85 Cholesterol, oxysterols, and cholesterol-rich vesicles were shown to activate complement.86 The cellular effects of complement activation in atherosclerosis require further definition, perhaps via transgenic models.
The possibility of excessive cholesterol buildup within cell membranes in the vicinity of the core needs to be evaluated. Under ordinary circumstances, most cells keep their plasma membrane content of cholesterol closely regulated somewhere between 0.4 and 0.8 mol per mole of phospholipid, depending on cell type.87 Phosphatidylcholine is the chief phospholipid of cell membranes, and physicochemical studies have shown that ratios of cholesterol to phosphatidylcholine up to 1.0 can exist in membranes before phase separation and the formation of cholesterol monohydrate crystals occurs.88 The sphingomyelin-rich vesicles found in the atherosclerotic core have higher levels of free cholesterol, up to 2.5 mol per mole of total phospholipid.52 53 Cholesterol can diffuse via the aqueous phase at slow but meaningful rates (aqueous solubility, 3x10-8 mol/L), thus partitioning among vesicles, crystals, and cell membranes within a limited area.89 In particular, the presence of crystals in the atherosclerotic core suggests that membranes in the vicinity might become physicochemically saturated with cholesterol at a level much higher than the physiological level for cell membranes.
One can also predict that lipoproteins in the vicinity of cholesterol crystals may become physicochemically saturated with free cholesterol or even undergo phase alteration to become vesicles.90 91 These effects could impair reverse cholesterol transport at the tissue level because reverse cholesterol transport depends on physicochemical gradients to accomplish net transfer of cholesterol from cellular plasma membrane to cholesterol acceptors, including HDL.92 93 Impairment of reverse cholesterol transport in atherosclerotic tissue is a plausible but unproved hypothesis that needs detailed examination.
Considering this environment, what defense mechanisms are available to cells to prevent excessive accumulation of free cholesterol? Lesion cells may accumulate cholesterol via unregulated uptake of modified lipoproteins, via phagocytosis, or via passive transfer. The downregulation of LDL receptors and of cholesterol synthesis may not block the input of cholesterol from these sources. For reasons suggested above, export of free cholesterol via interaction with HDL may be impaired. One defense mechanism that clearly operates in atherosclerotic lesions is an increase in acylcoenzyme A:cholesterol acyltransferase (ACAT) activity leading to cytoplasmic cholesteryl ester accumulation. However, accumulation of cholesteryl ester, which creates one or more expanding oily droplet or droplets within the cell, cannot continue without limit. Pharmacological inhibition of ACAT has been proposed as a way of decreasing cholesteryl ester accumulation in atherosclerotic lesions. With this approach one must recognize the possibility of adverse cellular effects due to excessive buildup of free cholesterol.
A further recently described adaptation to a high cholesterol content in cells may be increased synthesis of sphingomyelin.94 Phospholipids in the atherosclerotic core are known to be greatly enriched in sphingomyelin.95 96 Alteration of sphingomyelin metabolism in vascular cells could have other, unexpected effects because sphingomyelin metabolites comprise a signal transduction pathway decreasing the activity of protein kinase C.97 The observation that ceramide, a hydrolysis product of sphingomyelin, can induce apoptosis in fibroblasts might provide a link between these lipids and cell death in the atherosclerotic core.98
If cellular defenses fail and plasma membrane cholesterol concentrations increase, derangement of membrane function can be expected.87 99 Increases in calcium flux and other alterations have been demonstrated in smooth muscle cells exposed to high concentrations of free cholesterol administered in cholesterol/phospholipid vesicles.100 Macrophages loaded with cholesterol in the presence of ACAT inhibitors showed evidence of toxicity.93 The content of macrophages in rabbit atherosclerotic lesions was reduced by administration of an ACAT inhibitor.101 Whether cholesterol-induced toxicity for macrophages might have played a role in this in vivo effect is speculative.
The oxidation of core lipids provides another avenue for cellular effects. Cytotoxicity from oxidized LDL has been ascribed recently to 7-keto-, 7-hydroxy-, and/or 7-hydroperoxycholesterol.7 8 All of these compounds have been identified among atherosclerotic lipids.8 62 Cellular responses to lipid oxidation products are well reviewed in the literature on lipoprotein oxidation.102 103 104
A wide range of cell activities has been studied in the context of atherosclerotic lesion development but usually not in specific relation to the core or its lipids. Macrophages are commonly localized at the lateral boundaries and sometimes in the interior of the core. This localization could reflect a contribution by macrophages to lipid deposition, but other possibilities are chemoattraction by lipid components or complement fragments for monocyte/macrophages, and perhaps a role for macrophages in lipid removal. Histologically, capillarization and calcification of lesions appear closely related to core development. Capillarization is clearly a secondary phenomenon, because the early core does not contain microvessels. Expression of bone-related genes has been found in macrophages and smooth muscle cells near the core, adjacent to sites of dense calcification.9 10 11 A review of the atherosclerotic core in the not too distant future should include new data on these and other cellular responses.
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Summary |
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TopIntroductionCore Initiation Is an...Both Free and Esterified...Lipoprotein Aggregation and...Formation of Cholesterol-Rich...Core Lipids Are Partially...Some Proteins Accumulate...Lipid and Protein Components...Summary References |
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In recent years the role of the atherosclerotic core in promoting plaque rupture has become well recognized. A new insight into core development is its origination early in atherogenesis, before formation of the fibrous plaque. The early core is associated with accumulation of vesicular lipid rich in free cholesterol. Later in core development, lipid deposits become more diverse. The weight of evidence points toward a direct extracellular process, probably lipoprotein aggregation and fusion, as the chief pathway of cholesteryl ester accumulation, although foam cell death may also contribute cholesteryl ester. The mechanism or mechanisms of formation of vesicular, cholesterol-rich deposits are unknown. Since the increase in free cholesterol is likely to have deleterious effects on cells bordering the core, the further elucidation of cellular and biochemical pathways leading to and responding to free cholesterol accumulation is of great importance. Complement activation and cellular stress responses are prominent in the vicinity of core lipids, but their pathogenetic roles remain to be established. Since the core appears so early in atherogenesis, these as well as other, yet to be determined cellular responses to core lipids, oxidized and unoxidized, could have a considerable effect on overall lesion development. Much remains to be learned about macrophage and smooth muscle responses, calcification, capillarization, and matrix protein alterations in the evolution of the core and surrounding arterial intima.
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Acknowledgments |
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The authors' work has been supported by National Institutes of Health (NIH) grants HL-29680 and HL-45619. Dr Guyton held a Research Career Development Award from the NIH during much of the work summarized here.
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Footnotes |
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Reprint requests to John R. Guyton, MD, Department of Medicine, Box 3510, Duke University Medical Center, Durham, NC 27710. E-mail guyto001@mc.duke.edu.
Received April 4, 1995; accepted October 30, 1995.
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References |
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P. Sartipy, G. Camejo, L. Svensson, and E. Hurt-Camejo Phospholipase A2 Modification of Low Density Lipoproteins Forms Small High Density Particles with Increased Affinity for Proteoglycans and Glycosaminoglycans J. Biol. Chem., September 3, 1999; 274(36): 25913 - 25920. [Abstract] [Full Text] [PDF]
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C. Balagopalakrishna, L. Paka, S. Pillarisetti, and I. J. Goldberg Lipolysis-induced iron release from diferric transferrin: possible role of lipoprotein lipase in LDL oxidation J. Lipid Res., July 1, 1999; 40(7): 1347 - 1356. [Abstract] [Full Text]
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J. K. Hakala, K. Oorni, M. Ala-Korpela, and P. T. Kovanen Lipolytic Modification of LDL by Phospholipase A2 Induces Particle Aggregation in the Absence and Fusion in the Presence of Heparin Arterioscler Thromb Vasc Biol, May 1, 1999; 19(5): 1276 - 1283. [Abstract] [Full Text] [PDF]
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I. J. Goldberg, W. D. Wagner, L. Pang, L. Paka, L. K. Curtiss, J. A. DeLozier, G. S. Shelness, C. S. H. Young, and S. Pillarisetti The NH2-terminal Region of Apolipoprotein B Is Sufficient for Lipoprotein Association with Glycosaminoglycans J. Biol. Chem., December 25, 1998; 273(52): 35355 - 35361. [Abstract] [Full Text] [PDF]
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M. Ala-Korpela, M. O. Pentikäinen, A. Korhonen, T. Hevonoja, J. Lounila, and P. T. Kovanen Detection of low density lipoprotein particle fusion by proton nuclear magnetic resonance spectroscopy J. Lipid Res., August 1, 1998; 39(8): 1705 - 1712. [Abstract] [Full Text]
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S. L. Schissel, G. A. Keesler, E. H. Schuchman, K. J. Williams, and I. Tabas The Cellular Trafficking and Zinc Dependence of Secretory and Lysosomal Sphingomyelinase, Two Products of the Acid Sphingomyelinase Gene J. Biol. Chem., July 17, 1998; 273(29): 18250 - 18259. [Abstract] [Full Text] [PDF]
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S. Marathe, S. L. Schissel, M. J. Yellin, N. Beatini, R. Mintzer, K. J. Williams, and I. Tabas Human Vascular Endothelial Cells Are a Rich and Regulatable Source of Secretory Sphingomyelinase. IMPLICATIONS FOR EARLY ATHEROGENESIS AND CERAMIDE-MEDIATED CELL SIGNALING J. Biol. Chem., February 13, 1998; 273(7): 4081 - 4088. [Abstract] [Full Text] [PDF]
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S. L. Schissel, X.-c. Jiang, J. Tweedie-Hardman, T.-s. Jeong, E. H. Camejo, J. Najib, J. H. Rapp, K. J. Williams, and I. Tabas Secretory Sphingomyelinase, a Product of the Acid Sphingomyelinase Gene, Can Hydrolyze Atherogenic Lipoproteins at Neutral pH. IMPLICATIONS FOR ATHEROSCLEROTIC LESION DEVELOPMENT J. Biol. Chem., January 30, 1998; 273(5): 2738 - 2746. [Abstract] [Full Text] [PDF]
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H. S. Seo, D. M. Lombardi, P. Polinsky, L. Powell-Braxton, S. Bunting, S. M. Schwartz, and M. E. Rosenfeld Peripheral Vascular Stenosis in Apolipoprotein E-Deficient Mice : Potential Roles of Lipid Deposition, Medial Atrophy, and Adventitial Inflammation Arterioscler Thromb Vasc Biol, December 1, 1997; 17(12): 3593 - 3601. [Abstract] [Full Text]
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F. Li and D. Y. Hui Modified Low Density Lipoprotein Enhances the Secretion of Bile Salt-stimulated Cholesterol Esterase by Human Monocyte-Macrophages. SPECIES-SPECIFIC DIFFERENCE IN MACROPHAGE CHOLESTERYL ESTER HYDROLASE J. Biol. Chem., November 7, 1997; 272(45): 28666 - 28671. [Abstract] [Full Text] [PDF]
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E. Hurt-Camejo, U. Olsson, O. Wiklund, G. Bondjers, and G. Camejo Cellular Consequences of the Association of ApoB Lipoproteins With Proteoglycans: Potential Contribution to Atherogenesis Arterioscler Thromb Vasc Biol, June 1, 1997; 17(6): 1011 - 1017. [Abstract] [Full Text]
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I. Tabas, S. Marathe, G. A. Keesler, N. Beatini, and Y. Shiratori Evidence That the Initial Up-regulation of Phosphatidylcholine Biosynthesis in Free Cholesterol-loaded Macrophages Is an Adaptive Response That Prevents Cholesterol-induced Cellular Necrosis. PROPOSED ROLE OF AN EVENTUAL FAILURE OF THIS RESPONSE IN FOAM CELL NECROSIS IN ADVANCED ATHEROSCLEROSIS J. Biol. Chem., September 13, 1996; 271(37): 22773 - 22781. [Abstract] [Full Text] [PDF]
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W.-Y. Zhang, I. Ishii, and H. S. Kruth Plasmin-mediated Macrophage Reversal of Low Density Lipoprotein Aggregation J. Biol. Chem., October 13, 2000; 275(42): 33176 - 33183. [Abstract] [Full Text] [PDF]
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