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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:1011-1017.)
© 1997 American Heart Association, Inc.

Articles

Cellular Consequences of the Association of ApoB Lipoproteins With Proteoglycans

Potential Contribution to Atherogenesis

Eva Hurt-Camejo; Urban Olsson; Olov Wiklund; Göran Bondjers; ; Germán Camejo

From the Wallenberg Laboratory for Cardiovascular Research, Faculty of Medicine, University of Gothenburg, (E.H.-C., U.O., O.W., G.B., G.C.), and Astra Hässle AB, Preclinical Research Laboratories, Mölndal (G.C.), Sweden.

Correspondence to Germán Camejo, Astra Hässle AB, Preclinical Research Laboratories, Mölndal, S-431 83, Sweden.

Key Words: proteoglycans • atherogenesis • apoB lipoproteins

	ApoB Lipoproteins in the Intima and Atherosclerosis

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The hypothesis of a causal relation between disturbances of apoB lipoprotein metabolism and atherosclerosis is consistent with results from recent intervention studies with drugs that lower circulating levels of the lipoproteins.^{1 2 3} However, the molecular and cellular mechanisms by which apoB lipoproteins (LDL and VLDL) contribute to atherosclerosis are still unclear. Faber⁴ in 1949 concluded, with remarkable intuition, that cholesterol carried by lipoproteins colocalizes with CSs of the intima and that this accumulation contributes to lesion development. All sulfated polysaccharides, the GAGs, occur in the arterial intima and media as glycoproteins known generically as PGs.⁵ Immunohistochemical studies confirm the colocalization of the lipoproteins with extracellular GAGs in human and animal lesions.^{6 7} Hollander⁸ in 1976 suggested that GAGs of the intima are central for apoB lipoprotein accumulation in the extracellular intima and the subsequent tissue response. Analysis of lipids and lipoproteins indicates that most of the extracellular lipids of human lesions originate from plasma apoB lipoproteins.⁹ Isolation of only partially altered apoB lipoproteins from lesions also indicates that they are mostly associated with extracellular matrix elements, because if taken up by cells they should be rapidly degraded.^{10 11 12 13 14} Quantitative autoradiography likewise reveals that a large fraction of LDL in arteries resides in the extracellular intima in rabbits.¹⁵ Remarkable electron micrographs obtained by Nievelstein-Post et al¹⁶ also indicate that in rabbit intima LDL is associated with extracellular fibrillar structures, probably PGs. With the aid of high-resolution immunogold, Galis et al¹⁷ demonstrated that also in rabbits apoB lipoproteins colocalize with CSPG.

However, deposition and colocalization with PGs in the intima do not explain why this phenomenon should be atherogenic. Deposits of cholesterol and cholesteryl esters in the interstitial intima originated from apoB lipoproteins could be direct cytotoxic agents initiating the tissue reaction in atheromas.^{18 19} Additionally, structurally modified apoB lipoproteins or their oxidative and hydrolytic products may be triggers of the tissue response associated with atherogenesis.²⁰ Williams and Tabas,²¹ in what was termed "the response-to-retention hypothesis of early atherogenesis," recently discussed the general concepts of how apoB lipoprotein deposition in the intima may contribute to atherogenesis. Therefore, the present review is focused on the molecular aspects of the interaction of apoB lipoproteins with PGs of the intima and their potentially atherogenic cellular consequences.

	Molecular Basis for Entrapment of ApoB Lipoproteins in the Arterial Wall

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Pioneering work indicates that apoB lipoproteins interact with GAGs via associations of negative sulfate groups of GAGs and positive charges of the lysines (Lys, K) and arginines (Arg, R) of the apoB.^{22 23 24 25} Furthermore, LDL subfractions with high average pI, which are more positive, have the highest affinity for arterial PGs. The balance of Arg, Lys, Glu, Asp, and His side chains of the apoB-100 segments in the surface of apoB lipoproteins is the main determinant of pI. However, other surface groups, as N- and O- sialyl groups, also modulate the lipoproteins' surface charge and therefore their interaction with PGs of the human aortic intima in vitro and probably in vivo.^{26 27 28} Isolation of large peptide fragments of apoB-100 with positive regions that retained affinity for GAGs indicates that there are specific sequences of apoB-100 that bind them.^{29 30} The elucidation of the primary sequence of apoB-100³¹ allowed the search for segments that could reside in the particle surface and that have or do not have an excess of Arg, Lys, and His.^{32 33} Results from affinity chromatography and competition experiments with synthetic analogues of such segments suggest that the apoB-100 region 3359-3367 (RLTRKRGLK) is one of those with highest affinity with CS-rich arterial PGs and isolated C6S.^{32 34} For a detailed discussion on GAGs and protein association see the review by Jackson et al.³⁵

Addition of hydrophobic segments of valine (V) and tryptophan (W) at the N- and C- terminals of the apoB-100 segment 3359-3367 (VVW-RLTRKRGLK-VVV) allowed its attachment on the surface of neutral liposomes, LDL, and VLDL. The liposomes, which show no affinity for GAGs, acquire this property when the peptide is attached. The complex liposome-peptide has a higher affinity for C6S than the isolated peptide. Furthermore, LDL and VLDL increase their affinity for C6S when additional peptide copies are bound to them.³⁶ This behavior suggests that anchoring the GAG-binding segment to a polar lipid interface orients the Arg and Lys side chains for maximal interaction with the SO₄^- and COO^- of the C6S. Recent data indicate that segments of apoB-100, 3147-3157 (SVKAQYKKNKHRKH) and 3359-3367 (RLTRKRGLK), may act cooperatively in the association with PGs and GAGs.³⁷ These two segments, separated linearly by 202 amino acids, may be brought together by turns of the apoB-100 imposed by a disulfide bridge linking Cys(3167) and Cys(3297).³¹ Possibly apoB-100 becomes a better ligand for GAGs when the VLDL and LDL particles become smaller, because two or more positive segments coalesce in the particle's surface or become more exposed (Fig 1).^{36 37 38}

View larger version (42K): [in this window] [in a new window]   Figure 1. Diagram of how size and surface monolayer content of phospholipids (Phl) and free cholesterol (chol) of LDL may modulate the exposure and distribution of GAG-binding segments of apoB-100. In smaller, polar lipid–poor particles with high CSPG affinity, the positive segments may be allowed to coalesce into larger positive patches or may better expose the Arg/Lys side chains.

	Arterial PGs That Can Interact With ApoB Lipoproteins

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The intima contains different PGs distributed in specific locations. Versican, the most abundant PG of the intima, is a large member of the aggrecan family. It has a core protein of 263 kD and 15 to 20 GAG chains made of 70% C6S, 20% C4S, and 10% DS and is defined as a CSPG. It fills the essentially acellular intima as an extended tridimensional network in association with hyaluronate and provides the compressive resilience of the vessel wall. Two small PGs, decorin and biglycan, with core proteins of 36 kD and two to three GAG chains of DS, exist also in the intimal interstitium and are involved in the correct organization of collagen fibers. These PGs are mostly products of smooth muscle cells of the media. The basement membrane of the endothelium contains perlecan, with a large multidomain core protein (450 kD) and with three HS chains that interact with collagen type IV, vitronectin, and laminin. Syndecan is an additional PG associated with the plasma membrane of most cells, and it contains three to five CS and HS GAG chains attached to a 30-kD core protein. Its main function appears to be the accretion at the cell surface of growth factors, cytokines, lipases, and homeostasis factors that have GAG-binding segments. For a detailed discussion of vascular extracellular matrix, see the review by Wight.⁵

All PGs and sulfated GAGs can potentially interact with apoB lipoproteins, but the most studied is versican and the CS GAGs. During the proliferative phase of atherogenesis there is a marked increase in CSPG and most of the intima volume is occupied by the PGs and a collagen network.^{5 39 40} The CS and DS GAGs of lesion-prone regions of rabbits, pigeons, and humans have higher affinity for apoB lipoproteins than non–lesion-prone segments.^{41 42 43} Furthermore, the amount of LDL accumulated in aortas of hypercholesterolemic swine correlates with alterations of GAGs of the intima in lesion-prone regions.⁴⁴ In humans, this increased affinity is caused by longer CS chains in versican.⁴⁵ The origin of PG alterations of lesion-prone sites may be smooth muscle cells that begin to proliferate under the action of growth factors.^{46 47} This concept is supported by data showing that versican produced by proliferating human arterial smooth muscle cells in culture has a higher affinity for human LDL at physiological ionic composition and pH than that synthesized by nonproliferating cells.⁴⁸ The above findings could explain the increased retention time of LDL and the higher net accumulation of LDL and Lp(a) measured in vivo and in vitro in lesion-prone regions of rabbit aorta that precedes lesion development.^{49 50 51 52 53}

Small amounts of other active PGs, as heparin secreted by mast cells in the intima^{54 55} and CSPG, and heparan, secreted by macrophages, could also be important in complex formation with LDL in a growing lesion.⁵⁶ Moreover, macrophages from human cell lines secrete hypersulfated CSPG with longer CS chains than before differentiation. The CSPG has high affinity for lipoprotein lipase.⁵⁷ Such PGs could also increase the retention of apoB lipoproteins in the pericellular space via a ternary complex of PG, lipoprotein lipase, and LDL or directly as PG and LDL associations. In these complexes, Arg- and Lys-rich segments of apoB-100 also appear to be involved.^{58 59 60 61 62} Goldberg⁶³ recently reviewed this interesting development in detail.

	Structural Alterations of ApoB Lipoproteins Induced by PGs

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The interaction of LDL with PGs and GAGs induces structural alterations of LDL that remain after complex dissociation. At low ionic strength and physiological pH and Ca²⁺, LDL forms aggregates with arterial versican that can be dissociated into the soluble components by raising the NaCl concentration >140 mmol/L.⁶⁴ Although the resolubilized LDL shows no signs of aggregation, several structural modifications are introduced by the interaction. There is a decrease in the organization of the core and the surface monolayer of the LDL, indicated by reduction of the transition temperature of the cholesteryl ester core and the apoB-100.^{65 66} Additionally, there is an apparent increase in the exposure of Arg- and Lys-containing peptides, suggested by increased susceptibility to trypsin hydrolysis and increased binding to GAG.⁶⁶ One of the most interesting alterations of LDL induced by arterial versican and GAGs is an augmented sensitivity. Oxidized LDL can be isolated from the extracellular compartment of human lesions, and epitopes of oxidized apoB lipoproteins are found in the matrix of human lesions.^{67 68 69} Therefore, free radical–mediated oxidative modification of LDL may take place in the extracellular intima.^{70 71} Retention in the matrix may provide the time for the slow oxidation of LDL and also could potentiate these reactions. LDL that has been associated and dissociated from versican and GAGs shows a remarkable increase in the sensitivity to oxidation by Cu²⁺. This seems to be caused by augmented affinity of PG- and GAG-treated LDL for Cu²⁺.^{72 73} Moreover, LDL susceptibility to oxidation when incubated with human arterial smooth muscle cells and monocyte-derived macrophages was augmented by previous associating and dissociating from versican and C6S. This activity caused a significant increase of LDL uptake and degradation.⁷⁴ These effects may also reflect the capacity of PGs and GAGs for selecting small, dense LDLs that are more sensitive to oxidation than large, light ones, as discussed below.⁷⁵

LDL-PG complexes in different states of aggregation can be isolated from human and rabbit lesions.^{11 76 77} In vitro, depending on pH and Ca²⁺ concentration, irreversible aggregates of LDL can be formed with CSPG.⁷⁸ Increased time of residence of apoB lipoproteins by complex formation with PGs may also augment the chance for hydrolytic modifications by enzymes that reside in extracellular matrix or that can be secreted by cells of the intima. One of the earliest lipid alterations detected in apoB lipoproteins isolated from lesions is a reduction of the content of linoleic acid of phospholipids¹¹ and of phosphatidylcholine content compared with plasma LDL.^{12 13} This finding indicates that an sPLA₂ acts on the LDL in intima. Recently, Sartipy et al⁷⁹ found sPLA₂ in the extracellular matrix of human lesions, and the isolated enzyme used LDL phospholipids as substrates. Moreover, human sPLA₂ binds efficiently to C6S, which increases its activity toward LDL. Possibly, by colocalization of the enzyme and the lipoprotein, the CSPG of the intima may potentiate the degradation of LDL phospholipids.^{79 80} These results are interesting because lysolecithin produced by sPLA₂ may contribute to monocyte recruiting,⁸¹ reduce the production of nitric oxide,⁸² and promote cell proliferation, all actions thought to be atherogenic.⁸³ An additional enzyme that could contribute to the atherogenicity of the LDL trapped in the intima is sphingomyelinase. This enzyme, acting on LDL sphingomyelin, could increase the lipoprotein ceramide content and lead to its aggregation. Ceramides produced focally can be cell-proliferation modulators.⁸⁴

	Cellular Consequences of the Interaction of LDL With PGs

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The discussed modifications of LDL may affect the mechanisms for its uptake and degradation by cells of the intima. These effects of the interaction of LDL with PGs and GAGs were studied by association of LDL with human aortic versican and GAGs, followed by dissociation and reisolation of the lipoprotein. This procedure allows evaluation of only the effect of the PG-induced alterations of LDL, a model that may imitate the PG-modified LDL in the intima by formation of reversible associations. In vitro, PG-pretreated LDL is bound and internalized more efficiently by human monocyte-derived macrophages than native LDL. This causes appreciable intracellular accumulation of cholesterol, cholesteryl esters, triglycerides, and phospholipids and the appearance of lipid droplets in human monocyte-derived macrophages. The increase in intracellular lipids is produced by LDL uptake and by a marked stimulation of the endogenous synthesis of triglycerides, phospholipids, and cholesteryl esters.⁸⁵ Internalization of versican-treated LDL takes place via the apoB/E receptor and some other unidentified pathway(s) that is not the one used by acetylated LDL. This was not surprising, because no change in LDL charge is caused by the reversible association with arterial versican or C6S. However, uptake of PG-pretreated LDL does not downregulate the apoB/E receptor nor the hydroxymethylglutaryl-CoA reductase, as does native LDL. Such phenomena, which may contribute to lipid accumulation, suggest a divergence of the intracellular handling of PG-pretreated LDL from the one used for native LDL.⁷⁴ Human arterial smooth muscle cells also internalize and degrade more efficiently PG- or C6S-treated LDL than N-LDL, apparently via a combination of the apoB/E receptor and other unknown pathway(s) that are also not downregulable.^{74 86}

LDL, density 1.019 to 1.063 g/mL, is a heterogeneous population of particles.⁸⁷ The arterial versican has maximal affinity for dense LDL particles with the highest apoB-100 relative content, the lowest content of phospholipids and free cholesterol in their surface monolayer, and that are the most basic (higher pI). The denser subfractions with higher affinity for versican, once complexed and dissociated, also show higher uptake and degradation by human macrophages than larger, lighter subfractions.³⁸ We believe that because a smaller surface area of the particle is covered by phospholipids and free cholesterol, positive, PG-binding regions of apoB-100 become more accessible for the association (Fig 1). PGs possibly select these particles over the larger ones, and they may also be more susceptible to the GAG-induced structural alterations discussed above, resulting in a higher uptake by cells.³⁸ Small, dense LDL is more vulnerable to oxidative modifications.⁸⁸ This factor could also contribute to the increased sensitivity to oxidation observed in versican and GAG-selected LDL subfractions.^{72 74}

Vijayagopal et al⁸⁹ used a different model to study the effect of association of LDL with PGs. Complexes of apoB lipoprotein and CS-rich PGs, obtained from lesions or formed in vivo, were incubated directly with cells. This procedure may represent the interaction of cells with irreversible aggregates in the intima. Both types of complex are taken up efficiently by foam cells from rabbit lesions and human monocyte-derived macrophages. Scavenger receptors are mostly involved in the uptake that leads to appreciable cholesterol and cholesteryl ester accumulation. Although the electrophoretic mobility of the complex was not reported, they probably were more negative than native LDL. The same laboratory found that the apoB lipoprotein–PG complex in cocultures of macrophages and smooth muscle cells also was taken up efficiently and induced appreciable cholesteryl accumulation in both cells.⁹⁰

The GAG-binding regions of LDL appear to be included in the extended apoB/E receptor–binding region of apoB-100.^{31 37} Therefore, pericellular GAGs in the liver and other tissues may serve as a thin layer of high capacity and low affinity for accretion of LDL. From this layer, the high-affinity apoB/E receptor may more efficiently take up the lipoproteins.⁹¹ In the intima, which is made of a thick PG layer, the extracellular distribution will be favored and may be one of the reasons intimal thickening precedes atherosclerosis and no lesions are present in vessels without intima.⁹² Fig 2 presents a diagram of the hypothetical scenario suggested by the discussed findings. ApoB lipoproteins with high affinity for PGs increase their residence time by the formation of permanent or transient complexes. This provides the opportunity for structural, hydrolytic, and oxidative modifications of the lipoproteins with consequences for the cells of the intima. Such processes may have a physiological function for utilization and disposal of apoB lipoproteins by the arterial wall. However, when an excess of particles with high affinity for PGs circulates and enters the intima, the disposal system may be insufficient and gives opportunity for the initiation of the inflammatory and degenerative steps of atherogenesis.²¹

View larger version (44K): [in this window] [in a new window]   Figure 2. Scheme of the hypothetical atherogenic contribution of apoB lipoprotein retention by PGs. Lipoprotein particles with high affinity for versican and other PGs could form transient or irreversible complexes with the GAGs. The increased residence time could give opportunity for structural, oxidative, and enzymatic modifications of apoB lipoproteins. Products of such alterations may be cytotoxic to cells of the intima. Production of PGs with high affinity for apoB lipoproteins by smooth muscle cells and macrophages may contribute to chronicity of the process.

	Clinical Relevance of ApoB Lipoprotein Interactions With Arterial PGs

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High affinity of LDL for arterial CSPG in vitro could reflect tendency of the lipoprotein to interact with the intima, and this property could associate with atherogenesis. LDL is the main lipoprotein that forms insoluble aggregates when serum is incubated with arterial CSPGs, a simple test of affinity between the two macromolecules. Results from patients with acute coronary heart disease and subjects with apparent chronic coronary ischemia are consistent with the above hypothesis.^{93 94} In patients that suffered a myocardial infarction before 50 years of age, high affinity of LDL for CSPG was independently associated with the disease.⁹⁵ High affinity of LDL for CSPG seems to be associated with LDL fractions enriched in particles with high pI and a lower content of triglycerides.^{28 96} Fractionation of LDL from single subjects by their affinity to versican, or by gradient centrifugation, confirmed that the particles with higher affinity were poorer in surface polar lipids and were smaller, denser, and more basic than those with low affinity.³⁸ Recently Anber et al^{97 98} found that isolated small, dense LDL from patients with moderate hypertriglyceridemia and low HDL, defined as the "atherogenic lipoprotein phenotype," have high affinity for human arterial CSPG. The authors suggested that this property could explain in part the increased risk of coronary heart disease associated with this phenotype. It is not clear how many of the structural properties that modulate LDL affinity for CSPG are genetically determined, but diet and drugs can modify this property. Shifting subjects from an olive oil–rich diet to a polyunsaturated oil–rich diet increases the size of LDL and decreases the in vitro affinity for arterial versican.⁹⁹ In addition, nonpharmacological treatment of obese hypertensive patients reduces the LDL affinity for CSPG, independently of LDL levels.¹⁰⁰ Furthermore, apoB lipoprotein–lowering drugs, eg, simvastatin and gemfibrozil, also decreased the affinity, consequently suggesting that part of their antiatherogenic action may be associated with a reduced entrapment of LDL in the PGs of the intima.¹⁰¹

	Summary

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Many of the discussed results come from empirical experiments performed with in vitro models whose relevance to the complex environment of the intima is limited. However, they are consistent with the line of reasoning that intima PGs interact specifically with apoB lipoproteins and contribute to their retention. This could provide the residence time and the initial alterations of the lipoproteins that favor their further modifications by oxidative processes and hydrolytic enzymes. Products of such modifications, and the modified particles, may be stimuli for changes in the functionality of endothelium, smooth muscle cells, and macrophages. The focal synthesis of PGs with high affinity for apoB lipoproteins could make the phenomena chronic. Clinical and laboratory studies indicate that dense LDL, poor in surface polar lipids, is associated with an atherogenic phenotype. Particles with these properties may contribute to the disease via its high affinity for arterial PGs. This affinity can be modulated by diet, lifestyle, and lipid-lowering drugs.

	Selected Abbreviations and Acronyms

 

C6S = chondroitin-6-sulfate CS = chondroitin sulfate DS = dermatan sulfate GAG = glycosaminoglycan HS = heparan sulfate PG = proteoglycan pI = isoelectric point sPLA2 = secretory phospholipase A2

	Acknowledgments

 
The experimental work from our laboratories was generously supported by grants from the Swedish Medical Research Council, the Swedish Heart and Lung Foundation, the Swedish Medical Society, and Astra Hässle AB.

Received January 8, 1997; accepted January 22, 1997.

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