Structural, transport and optical properties of (La0.6Pr0.4)0.65Ca0.35MnO3 nanocrystals: a wide band-gap magnetic semiconductor.

(La0.6Pr0.4)0.65Ca0.35MnO3 system has been synthesized via a sol-gel route at different sintering temperatures. Structural, transport and optical measurements have been carried out to investigate (La0.6Pr0.4)0.65Ca0.35MnO3 nanoparticles. Raman spectra show that Jahn-Teller distortion has been decreased due to the presence of Ca and Pr in A-site. Magnetic measurements provide a Curie temperature around 200 K and saturation magnetization (MS) of about 3.43µB/Mn at 5 K. X-ray photoemission spectroscopy study suggests that Mn exists in a dual oxidation state (Mn(3+) and Mn(4+)). Resistivity measurements suggest that charge-ordered states of Mn(3+) and Mn(4+), which might be influenced by the presence of Pr, have enhanced insulating behavior in (La0.6Pr0.4)0.65Ca0.35MnO3. Band gap estimated from UV-Vis spectroscopy measurements comes in the range of wide band gap semiconductors (∼3.5 eV); this makes (La0.6Pr0.4)0.65Ca0.35MnO3 a potential candidate for device application.

Nitrobenzene compounds inhibit expression of VCAM-1.

A series of nitrobenzene compounds has been discovered as potent inhibitors of VCAM-1 expression and, therefore, potential drug candidates for autoimmune and allergic inflammatory diseases. Structure-activity relationship (SAR) studies showed that a nitro group and two other electron-withdrawing groups are essential for these compounds to be potent inhibitors of VCAM-1 expression.

Dithiocarbamates: effects on lipid hydroperoxides and vascular inflammatory gene expression.

Dithiocarbamates are a well-defined family of antioxidants that may have therapeutic uses such as in treatment of inflammation and atherosclerosis. A critical event in the pathogenesis of atherosclerosis is the infiltration of inflammatory cells into the vessel wall. Vascular cell adhesion molecule-1 (VCAM-1) plays a pivotal role in this process by mediating leukocyte binding to endothelial cells. VCAM-1 expression is stimulated by oxidized polyunsaturated fatty acids such as 13-hydroperoxy-octadecadienoic acid (13-HPODE), and this lipid hydroperoxide has been proposed to be a second messenger for induction of VCAM-1 gene expression. Pyrrolidine dithiocarbamate (PDTC) markedly represses cytokine-induced VCAM-1 gene expression in cultured human endothelial cells; however, its effects on the oxidative second messenger pathway are unknown. Using a lipoxygenase (LO) inhibition assay in tandem with a colorimetric assay for lipid peroxides, we determined that PDTC does not inhibit the enzymatic oxidation of linoleic acid to 13-HPODE by LO, but directly interacts with and chemically reduces 13-HPODE. We hypothesize that dithiocarbamates may intercept the oxidative second-messenger-induced expression of VCAM-1 and other redox-regulated genes important in inflammation and atherosclerosis.

Decreased secretion of ApoB follows inhibition of ApoB-MTP binding by a novel antagonist.

Apolipoprotein B (apoB) and microsomal triglyceride transfer protein (MTP) are essential for the efficient assembly of triglyceride-rich lipoproteins. Evidence has been presented for physical interactions between these proteins. To study the importance of apoB-MTP binding in apoB secretion, we have identified a compound, AGI-S17, that inhibited (60-70% at 40 microM) the binding of various apoB peptides to MTP but not to an anti-apoB monoclonal antibody, 1D1, whose epitope overlaps with an MTP binding site in apoB. AGI-S17 had no significant effect on the lipid transfer activity of the purified MTP. In contrast, another antagonist, BMS-200150, did not affect apoB-MTP binding but inhibited MTP's lipid transfer activity. The differential effects of these inhibitors suggest two functionally independent, apoB binding and lipid transfer, domains in MTP. AGI-S17 was then used to study its effect on the lipid transfer and apoB binding activities of MTP in HepG2 cells. AGI-S17 had no effect on cellular lipid transfer activities, but it inhibited coimmunoprecipitation of apoB with MTP. These studies indicate that AGI-S17 inhibits apoB-MTP binding but has no effect on MTP's lipid transfer activity. Experiments were then performed to study the effect of inhibition of apoB-MTP binding on apoB secretion in HepG2 cells. AGI-S17 (40 microM) did not affect cell protein levels but decreased the total mass of apoB secreted by 70-85%. Similarly, AGI-S17 inhibited the secretion of nascent apoB by 60-80%, but did not affect albumin secretion. These studies indicate that AGI-S17 decreases apoB secretion most likely by inhibiting apoB-MTP interactions. Thus, the binding of MTP to apoB may be important for the assembly and secretion of apoB-containing lipoproteins and can be a potential target for the development of lipid-lowering drugs. It is proposed that the apoB binding may represent MTP's chaperone activity that assists in the transfer from the membrane to the lumen of the endoplasmic reticulum and in the net lipidation of nascent apoB, and may be essential for lipoprotein assembly and secretion.

Perlecan mediates the antiproliferative effect of apolipoprotein E on smooth muscle cells. An underlying mechanism for the modulation of smooth muscle cell growth?

Apolipoprotein E (apoE) is known to inhibit cell proliferation; however, the mechanism of this inhibition is not clear. We recently showed that apoE stimulates endothelial production of heparan sulfate (HS) enriched in heparin-like sequences. Because heparin and HS are potent inhibitors of smooth muscle cell (SMC) proliferation, in this study we determined apoE effects on SMC HS production and cell growth. In confluent SMCs, apoE (10 microg/ml) increased (35)SO(4) incorporation into PG in media by 25-30%. The increase in the medium was exclusively due to an increase in HSPGs (2.2-fold), and apoE did not alter chondroitin and dermatan sulfate proteoglycans. In proliferating SMCs, apoE inhibited [(3)H]thymidine incorporation into DNA by 50%; however, despite decreasing cell number, apoE increased the ratio of (35)SO(4) to [(3)H]thymidine from 2 to 3.6, suggesting increased HS per cell. Purified HSPGs from apoE-stimulated cells inhibited cell proliferation in the absence of apoE. ApoE did not inhibit proliferation of endothelial cells, which are resistant to heparin inhibition. Analysis of the conditioned medium from apoE-stimulated cells revealed that the HSPG increase was in perlecan and that apoE also stimulated perlecan mRNA expression by >2-fold. The ability of apoE isoforms to inhibit cell proliferation correlated with their ability to stimulate perlecan expression. An anti-perlecan antibody completely abrogated the antiproliferative effect of apoE. Thus, these data show that perlecan is a potent inhibitor of SMC proliferation and is required to mediate the antiproliferative effect of apoE. Because other growth modulators also regulate perlecan expression, this may be a key pathway in the regulation of SMC growth.

Therapeutic strategies for coronary artery disease beyond low density lipoprotein (LDL)--lowering.

Coronary artery disease (CAD) ranks as the leading cause of death in the Western world. The most widely used therapeutics utilized for the treatment of CAD are the lipid-lowering drugs, which lower plasma cholesterol. However lowering cholesterol alone may not be sufficient to provide benefit to all patient populations at risk for CAD. This creates an unmet medical need. Emerging knowledge of the genesis, progression and regression of atherosclerosis, that leads to CAD permits evaluation of other therapeutic strategies. This review will evaluate two such naturally occurring paradigms, the nitric oxide pathway and the high-density lipoprotein system which are nature's defense mechanisms against atherosclerosis and may lead to next generation therapeutics against CAD.

Lipoprotein lipase greatly enhances the retention of lipoprotein(a) to endothelial cell-matrix.

The trapping of apolipoprotein (apo)B containing lipoproteins within the arterial subendothelial matrix (ECM) is an early event in atherosclerosis. When lipoprotein lipase, a constituent of the ECM, is prebound to ECM both LDL and oxidized LDL binding is greatly enhanced. In this study we compared the binding of lipoprotein(a) (Lp(a)), a lipoprotein correlated with atherosclerosis and restenosis, to ECM in the presence of varying concentrations of LPL. Without LPL, Lp(a) binding was low and non-saturable. In the presence of LPL, Lp(a) retention increased from 2.7 x 10(-7) to 1.13 x 10(-4) nmoles. Scatchard analysis demonstrated that the affinities of both Lp(a) and LDL to lipase were similar. In competition experiments, LDL, apoE, polymers of lysine and arginine were all capable of preventing the lipase specific [125I]Lp(a) retention. However, neither collagen nor fibronectin were capable of blocking or displacing [125I]Lp(a) from the lipase bound to ECM. In a separate set of experiments, when ECM was not saturated with lipase, both fibronectin and collagen (at 10-fold protein excess) prevented approximately 40% of total [125I]Lp(a) retention to ECM. These data suggest, in the absence of lipase, apo(a) may regulate the binding of Lp(a) to ECM. Whereas, lipase enhanced the binding of Lp(a) to ECM, most probably through the apoB moiety of the Lp(a) particle.

Hypertensive disorders of pregnancy and maternal and foetal outcome: a case controlled study.

A case controlled prospective study of 250 cases of hypertension complicating pregnancy (study group) and 400 normal pregnant women (control group) was carried out to determine the effect of hypertension on maternal and foetal outcome. Pregnancy induced hypertension was present in 96% cases and chronic hypertension in 4% cases. Preterm delivery (28.8% versus 3%), labour induction rate (52.8% versus 3.25%), caesarean section rate (14.8% versus 3.5%), stillbirth rate (4.8% versus 0.25%) and overall perinatal mortality rate (14.8% versus 1%) were higher in study group compared to controls. In study group (40%) babies required special nursery care compared to controls (6.75%). From these results it can be concluded that maternal hypertension is associated with adverse pregnancy outcome.

PIP: The effect of hypertension on maternal and fetal outcome was investigated in a case-control study of 250 pregnant women with hypertension (average age, 23.8 years) and 400 pregnant women without this complication (average age, 22.1 years) who presented to Safdarjang Hospital in New Delhi, India. 200 cases (80%) and 372 controls (93%) were primigravidae. 240 cases (96%) had pregnancy-induced hypertension, while 10 (4%) had chronic hypertension. Hypertension was mild and nonproteinuric in 142 cases (56.8%), and was severe and proteinuric in 108 (43.2%). As expected, the prevalence of adverse outcomes was significantly higher in cases than controls: preterm delivery, 28.8% vs. 3%; need for labor induction, 52.8% vs. 3.25%; cesarean section delivery, 14.8% vs. 3.5%; and need for special nursery care, 40% vs. 6.75%. 4.8% of infants of mothers with hypertension were stillborn, compared with 0.25% of infants of controls; overall perinatal mortality rates were 14.8% and 1%, respectively. All neonatal complications occurred in proteinuric, pregnancy-related hypertension cases and there was a strong association between perinatal loss and both prematurity and low birth weight. Maternal hypertension contributes to an estimated 22% of all perinatal deaths. This risk could be reduced by optimum antenatal care and timely increased use of obstetric interventions.

Selective inhibition of tumor necrosis factor-induced vascular cell adhesion molecule-1 gene expression by a novel flavonoid. Lack of effect on transcription factor NF-kappa B.

In the present studies, we examined the effect of flavonoids on the endothelial cell expression of adhesion molecules, an early step in inflammation and atherogenesis. Addition of tumor necrosis factor-alpha (TNF) to human aortic endothelial cells (HAECs) led to the induction of vascular cell adhesion molecule-1 (VCAM-1) expression and enhancement in expression of intercellular adhesion molecule-1 (ICAM-1). A flavonoid, 2-(3-amino-phenyl)-8-methoxy-chromene-4-one (PD 098063), markedly inhibited TNF-induced VCAM-1 cell-surface expression in a concentration-dependent fashion with half-maximal inhibition at 19 mumol/L but had no effect on ICAM-1 expression. Another structurally distinct flavonoid, 2-phenyl-chromene-4-one, similarly selectively decreased VCAM-1 expression. The inhibition in cell-surface expression of VCAM-1 by PD 098063 correlated with decreases in steady-state mRNA levels, but there was no effect on ICAM-1 mRNA levels. The decrease in VCAM-1 mRNA levels was not due to changes in mRNA stability but rather resulted from a reduction in the rate of transcription of the gene. However, electrophoretic mobility shift assays using nuclear extracts from TNF-induced HAECs treated with PD 098063 failed to show a decrease in the activation of NF-kappa B, indicating that inhibition of activation of this transcription factor may not be its mode of action. Similarly, PD 098063 did not affect chloramphenicol acetyltransferase reporter gene activity in TNF-inducible minimal VCAM-1 promoter constructs containing two NF-kappa B sites, suggesting that the compound does not affect the transactivation driven by these sites. We conclude that this compound selectively blocks agonist-induced VCAM-1 protein and gene expression in HAECs by NF-kappa B-independent mechanism(s).

Transient overexpression of human 15-lipoxygenase in aortic endothelial cells enhances tumor necrosis factor-induced vascular cell adhesion molecule-1 gene expression.

15-lipoxygenase (15-LO) expression in artery wall cells has been demonstrated during the development of atherosclerosis in various animal models. We examined whether the expression of 15-LO in aortic endothelial cells affects the gene expression of the adhesion molecule, vascular cell adhesion molecule-1 (VCAM-1). Transient transfection of human 15-LO cDNA into bovine aortic endothelial cells led to the expression of 15-LO protein and enzymatic activity. We studied the induction of VCAM-1 mRNA in these cells. 15-LO expressing cells showed no detectable levels of VCAM-1 message. However, when TNF was added to these cells there was a synergistic increase in VCAM-1 expression relative to cells that were transfected with control plasmid pcDNA I. Our data suggest that 15-LO expression in aortic endothelium may amplify the expression of VCAM-1 induced by inflammatory stimulus during atherogenesis.

Oxidation of low density lipoproteins greatly enhances their association with lipoprotein lipase anchored to endothelial cell matrix.

Native and oxidized low density lipoprotein retention within arterial wall endothelial cell matrix (ECM) is an early event in the pathogenesis of atherosclerosis. Previously we showed lipoprotein lipase (LPL) addition to ECM enhanced the retention of apoB-containing lipoproteins. In the present studies we examined whether the oxidation of low density lipoprotein (LDL) increases its retention by LPL-containing ECM. Except where noted, 125I-labeled moderately oxidized LDL (ModOxLDL) was prepared by long term storage of 125I-LDL. Without LPL, 125I-ModOxLDL matrix binding was low and nonsaturable. LPL preanchored to ECM resulted in 125I-ModOxLDL binding that was saturable and 20-fold greater than in the absence of LPL, with an association constant equal to 2.6 nM. Copper-oxidized LDL (Cu-OxLDL) was able to compete with 125I-ModOxLDL, whereas a 60-fold native LDL excess had no effect. Reconstituted apolipoprotein B from Cu-OxLDL also reduced 125I-ModOxLDL to LPL, whereas liposomes derived from the lipid extract of Cu-OxLDL had no effect on binding. These data suggest that the increased binding of oxidized LDL to LPL-ECM may be due to the exposure of novel apoB binding sites and not an oxidized lipid moiety. 125I-ModOxLDL binding was also not affected by either preincubation with a 300-fold molar excess of apoE-poor HDL or an 340-fold molar excess of Cu-Ox-HDL. In contrast, a 4-fold apoE-rich HDL excess (based on protein) totally inhibited 125I-ModOxLDL matrix retention. Positively charged peptides of polyarginine mimicked the effect of apoE-rich HDL in reducing the 125I-ModOxLDL retention; however, polylysine had no effect. We postulate that the oxidation of LDL may be a mechanism that enhances LDL retention by the ECM-bound LPL and that the protective effects of apoE-containing HDL may in part be due to its ability to block the retention of oxidized LDL in vivo.

Identification of a novel 85-kDa lipoprotein lipase binding protein on human aortic endothelial cell surface.

Lipoprotein lipase (LPL), bound to the luminal surface of vascular endothelium catalyzes lipoprotein triglyceride hydrolysis. Studies were performed to identify human aortic endothelial (HAEC) cell-surface proteins having high affinity for LPL. LPL-sepharose affinity chromatography of [35S]O4 labeled HAEC proteins identified a 220-kDa proteoglycan. Ligand blotting of HAEC plasma membrane proteins with LPL revealed two specific binding proteins of MW 116 kDa and 85 kDa, respectively, which were not released from the cell-surface by heparin treatment. Since the 220-kDa and 116-kDa proteins have been reported previously in bovine endothelial cells, we focused on the 85-kDa protein. The 85-kDa protein was not labelled by incubation of the cells with [35S]O4, suggesting that it is not a sulfated proteoglycan. Treatment of HAEC with tunicamycin markedly decreased detection of the 85-kDa protein, suggesting that it is likely a glycoprotein synthesized by HAEC. We conclude that HAEC cell surface has three specific LPL binding proteins, a 220-kDa proteoglycan, a 116-kDa protein and a novel 85-kDa protein.

Inhibition of tumor necrosis factor induced human aortic endothelial cell adhesion molecule gene expression by an alkoxybenzo[b]thiophene-2-carboxamide.

The effects of a novel anti-inflammatory agent, 5-methoxy-3-(1-methyl-ethoxy)benzo[b]thiophene-2-carboxamide-1-oxide (PD 144795) on adhesion molecule expression in tumor necrosis factor (TNF) stimulated human aortic endothelial cells (HAEC) were examined. PD 144795 treatment markedly inhibited the TNF-induced cell expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) protein and mRNA. Gel shift assays using nuclear extracts from HAEC treated with PD 144795 failed to show a decrease in the activation of NFkB by this compound, whereas pyrrolidine dithiocarbamate (PDTC), an antioxidant, markedly inhibited the activation of this transcription factor. Thus, PD 144795 inhibits agonist-stimulated VCAM-1 and ICAM-1 expression likely via an NFkB independent mechanism, distinct from that of PDTC. Such agents may provide a novel approach for control of adhesion molecule gene expression in inflammation.

Apolipoprotein B and E basic amino acid clusters influence low-density lipoprotein association with lipoprotein lipase anchored to the subendothelial matrix.

Lipoprotein accumulation in the subendothelial matrix is an important step in atherogenesis. We have previously shown that addition of lipoprotein lipase (LPL) markedly increased binding of apolipoprotein B (apoB)-containing lipoproteins to an endothelial cell-derived matrix, and this enhanced lipoprotein binding was inhibited by apoE. In the present studies we examined the role of various regions of apoB in the binding of LDL to LPL-containing endothelial cell matrix and the ability of various apoE domains to decrease lipoprotein retention. We studied three apoB epitope-specific monoclonal antibodies for their ability to block the binding of 125I-LDL to LPL-containing matrix. Of these, monoclonal antibody 4G3, which recognizes an arginine-containing epitope in apoB, was the most effective in reducing LDL binding. Chemical modification of LDL apoB lysines or arginines markedly reduced the ability of the lipoprotein to block the binding of 125I-LDL to LPL-containing matrix, suggesting that apoB positively charged amino acids are involved in the interaction. Furthermore, polyarginine or polylysine markedly decreased 125I-LDL binding to LPL-containing matrix, whereas polyleucine was ineffective. These data suggest that apoB positively charged regions are important in LDL binding. To explore the role of charge modifications on apoE by single arginine-cysteine interchanges, we examined the effects of the three major human apoE isoforms (apoE2, apoE3, and apoE4). ApoE3 was the most effective in decreasing 125I-LDL retention, followed by apoE4; apoE2 was the least effective. Similarly, apoE2-containing HDL was much less effective than apoE3-containing HDL in decreasing 125I-LDL retention.(ABSTRACT TRUNCATED AT 250 WORDS)

Acyl-coenzyme A:cholesterol-acyltransferase (ACAT) inhibitors modulate monocyte adhesion to aortic endothelial cells.

Increased monocyte adhesion to aortic endothelium is observed in the pathogenesis of atherosclerosis. The role of endothelial acyl-coenzyme A:cholesterol-acyltransferase (ACAT) in the regulation of monocyte adhesion is not known. To examine the potential role of this enzyme in monocyte adhesion, a specific ACAT inhibitor, CI-976, was utilized. Although the basal adhesion of U937 monocytic cells to porcine aortic endothelial cells was low, treatment of the endothelial cells with lipopolysaccharide (LPS) markedly increased monocyte adhesion. Monocyte adhesion to LPS-treated endothelial cells was markedly inhibited by CI-976 treatment of the endothelial cells. Similarly, another ACAT inhibitor, PD 132301-2, whose structure is distinct from CI-976, also decreased monocyte adhesion. CI-976 treatment of endothelial cells also decreased endothelial cell ACAT activity. Since leukotriene B4 (LTB4) is known to promote leukocyte-endothelial cell adhesion, endothelial cell production of this leukotriene was examined after incubation with CI-976. CI-976 treatment markedly decreased LTB4 synthesis. Exogenous LTB4 addition to CI-976 treated cells reversed the effects of this compound on monocyte adhesion. These data demonstrate that ACAT inhibitors decrease monocyte adhesion to endothelial cells. Similar mechanisms may contribute to antiatherosclerotic effects of ACAT inhibitors in vivo.

Endothelial cells and atherosclerosis: lipoprotein metabolism, matrix interactions, and monocyte recruitment.

The endothelial cell and subendothelial cell matrix provide a stage for several interactions that mediate lipoprotein transport, retention, and modification during atherogenesis. Many novel mechanisms in these processes have been uncovered. The endothelium regulates circulating plasma lipoproteins by acting as the site of action of the triglyceride hydrolyzing enzyme, lipoprotein lipase. Endothelial cells synthesize proteoglycans that anchor this enzyme, affect the actions of growth factors, and directly interact with some classes of lipoproteins. Recent studies have provided insights into the initiation of monocyte entry and the regulation of macrophage lipid uptake. Endothelial cell adhesion molecules are required for the recruitment of monocytes and, therefore, are essential to the atherosclerotic process. Understanding cellular and molecular pathways underlying the early stages of atherosclerosis may provide a rational basis for therapeutic intervention of this disease.

Lipoprotein lipase facilitates very low density lipoprotein binding to the subendothelial cell matrix.

The effect of bovine lipoprotein lipase (LPL) on very low density lipoprotein (VLDL) binding to subendothelial matrix was studied. Without LPL, VLDL bound poorly to the matrix. However, decreasing NaCl or elevating Ca++ concentration increased matrix VLDL binding. With LPL, VLDL binding was markedly increased. Since LPL is a normal constituent of the artery wall and is elevated in atherosclerotic lesions, we postulate two potential mechanisms for the involvement of VLDL and LPL in atherogenesis. First, VLDL acquisition is attenuated by the increased matrix LPL content in the developing atheroma. Secondly, elevated plasma levels of VLDL (and VLDL remnants) such as in Type II or III dyslipidemia could enhance such interactions. These events likely accelerate the rate of atherosclerosis lesion development.

Apolipoprotein E modulates low density lipoprotein retention by lipoprotein lipase anchored to the subendothelial matrix.

Lipoprotein lipase (lipase), a key enzyme in lipoprotein triglyceride metabolism, has been shown to markedly increase low density lipoprotein (LDL) retention by subendothelial matrix. In the present study we assessed the role that lipoprotein and matrix components play in retention of LDL by lipase anchored to the subendothelial matrix. Lipase addition to subendothelial matrix increased LDL retention by 66-fold. Scatchard analysis of LDL binding to lipase-containing matrix yielded an association constant of 12 nM. Exogenous addition of the matrix components, heparan sulfate and dermatan sulfate (i.e. chondroitin sulfate B), reduced LDL retention by greater than 90%. These glycosaminoglycans (GAGs) also reduced lipolytic activity associated with the matrix, suggesting that lipase was released from its binding sites on the matrix. In contrast, other matrix components (collagen, fibronectin, vitronectin, and chondroitin sulfate A) neither affected LDL release nor matrix lipolytic activity. Thus, heparan sulfate and dermatan sulfate function to anchor lipase to the subendothelial cell matrix. The effects of apolipoprotein E (apoE) and apoA-I were also examined. Preincubation of the subendothelial matrix with apoE, followed by washing, did not affect subsequent lipase binding to the matrix nor its ability to retain LDL. However, the direct addition of apoE alone or in combination with phospholipid liposomes decreased lipase-mediated LDL retention in a concentration-dependent fashion. Addition of apoA-I had no effect. Thus, in these studies apoE functions to displace LDL bound to lipase, but not lipase anchored to the matrix. To further examine the physiologic implications of this process, we assessed the ability of human apoE-rich and apoE-poor high density lipoproteins (HDL) to displace LDL from matrix-anchored lipase. ApoE-rich HDL reduced LDL retention dramatically (86% at 2.5 micrograms/ml). In contrast, apoE-poor HDL, at the highest concentration evaluated (400 micrograms/ml), decreased LDL retention by only 32%. Overall, these data suggest apoE and specifically apoE-containing HDL reduce the lipase-mediated retention of LDL by subendothelial matrix. This observation, in part could explain the protective effects of apoE and apoE-containing HDL against atherosclerosis.