Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The surface sialic acid content of aortic endothelial cells in vitro was substantially lower in sparse cultures than at confluence. Binding of LDL to endothelial cells did not change at different culture densities and was unaffected by brief pretreatment with neuraminidase to partially remove surface sialic acid residues. In contrast, internalization of LDL declined by a factor of 3 between low density cell cultures and confluent monolayers; neuraminidase pretreatment increased LDL uptake and the effect was most marked (greater than 10-fold) at confluence. Pretreatment with cationised ferritin, which removed most of the surface sialic acid residues as well as glycosaminoglycans, increased LDL internalization by up to 20-fold, again with most effect on confluent monolayers. Thus LDL uptake is inversely correlated with sialic acid content. We conclude that changes in the surface density of sialic acid (and possibly other charged) residues significantly modulate endothelial LDL uptake, and suggest that focal increases in LDL accumulation during atherogenesis may be related to alterations in endothelial endocytic properties at sites of increased cell turnover or damage.
Atherosclerosis 1984 Oct
PMID:Surface determinants of low density lipoprotein uptake by endothelial cells. 649 41

This preliminary study describes effects of two pharmacologic agents on erythrocyte behavior. Increased erythrocyte aggregation has been proposed as important in the pathogenesis of a number of disorders, but the exact mechanism by which it plays a role in disease production remains unclear. Several anionic amphophiles have been reported to benefit diabetic vascular disease and atherosclerosis. If anionic amphophiles enter the erythrocyte plasma membrane they can increase its negative charge, reducing the energy of attraction between red blood cells and diminishing erythrocyte aggregation. Erythrocytes were studied after suspension in phosphate-buffered saline containing dextran as an aggregation-promoting agent. A marginal reduction of the suspension's viscosity was found at low shear rate when 2,5- dihydroxybenzene sulfonate was added. Additionally, erythrocyte sedimentation rate was marginally influenced. Both dihydroxybenzene sulfonate and acetylsalicylate protected human erythrocytes from hemolysis at concentrations from 10(-3) to 10(-5) M. The removal of erythrocyte sialic acid using neuraminidase to reduce surface negative charge led to unequivocal interference with aggregation (MAI technique of CHIEN et al., J. Gen. Physiol., 1973) by both anionic amphophiles were studied. Dihydroxybenzene sulfonate and actylsalicylate reduced the aggregation propensity of sialic-free erythrocytes, suggesting that the effect on the low shear rate viscosity of sialic acid-containing erythrocytes, though modest, is real.
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PMID:Effect of anionic amphophiles on erythrocyte properties. 658 20

This study was undertaken to determine whether sialic acid removal alters the catabolism of low density lipoprotein in humans. Human low density lipoproteins labeled in vitro with 125I were incubated in the presence (termed desialylated) or absence (sialylated) of neuraminidase. The treatment with neuraminidase from Clostridium perfringens removed 90% of the sialic acid residues which did not change the chemical composition of the lipoproteins. Sialylated or desialylated LDL were injected intravenously into normal human subjects. The mathematical analysis of the plasma radioactivity decay curves (followed for 220 h) of desialylated low density lipoproteins, when compared with sialylated LDL, showed a shorter mean transit time (51 h vs 60 h), a 52% faster metabolic catabolic rate and an increased volume of distribution. The data are consistent with a proposed metabolism of low density lipoproteins: in humans, desialylation appears to accelerate the first step of the low density lipoprotein conversion but not to alter its final catabolism.
Atherosclerosis 1980 Oct
PMID:Effect of sialic acid removal on human low density lipoprotein catabolism in vivo. 742

Combined treatment with trypsin, cholesterol esterase, and neuraminidase transforms LDL, but not HDL or VLDL, to particles with properties akin to those of lipid extracted from atherosclerotic lesions. Single or double enzyme modifications, or treatment with phospholipase C, or simple vortexing are ineffective. Triple enzyme treatment disrupts the ordered and uniform structure of LDL particles, and gives rise to the formation of inhomogeneous lipid droplets 10-200 nm in diameter with a pronounced net negative charge, but lacking significant amounts of oxidized lipid. Enzymatically modified LDL (E-LDL), but not oxidatively modified LDL (ox-LDL), is endowed with potent complement-activating capacity. As previously found for lipid isolated from atherosclerotic lesions, complement activation occurs to completion via the alternative pathway and is independent of antibody. E-LDL is rapidly taken up by human macrophages to an extent exceeding the uptake of acetylated LDL (ac-LDL) or oxidatively modified LDL. After 16 h, cholesteryl oleate ester formation induced by E-LDL (50 micrograms/ml cholesterol) was in the range of 6-10 nmol/mg protein compared with 3-6 nmol/mg induced by an equivalent amount of acetylated LDL. At this concentration, E-LDL was essentially devoid of direct cytotoxic effects. Competition experiments indicated that uptake of E-LDL was mediated in part by ox-LDL receptor(s). Thus, approximately 90% of 125I-ox-LDL degradation was inhibited by a 2-fold excess of unlabeled E-LDL. Uptake of 125I-LDL was not inhibited by E-LDL. We hypothesize that extracellular enzymatic modification may represent an important step linking subendothelial deposition of LDL to the initiation of atherosclerosis.
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PMID:On the pathogenesis of atherosclerosis: enzymatic transformation of human low density lipoprotein to an atherogenic moiety. 750 42

The effect of Lp(a) on lipid metabolism in cells cultured from unaffected human aortic intima has been investigated. Lp(a) isolated from the blood of healthy subjects failed to alter intracellular neutral lipid content. On the other hand, Lp(a) obtained from coronary atherosclerosis patients induced a 1.5- to 2-5-fold increase in intracellular levels of free and esterified cholesterol and triglycerides. The sialic acid content of patients' Lp(a) was 2.5-fold lower as compared with that of healthy subjects' Lp(a). Healthy donors' Lp(a) in vitro desialylated with neuraminidase were able to accumulate lipids within the cells. Using lectin-chromatography on Ricinus Communis agglutinin-agarose, Lp(a) was divided into subfractions differing by sialic acid content. Desialylated (sialic acid-poor) Lp(a), but not sialylated lipoproteins, were capable of increasing the intracellular content of total cholesterol. Desialylated but not sialylated Lp(a) formed aggregates during incubation under cell culture conditions. Isolated aggregates of desialylated Lp(a) induced lipid accumulation in cells. Elimination of Lp(a) aggregates from cultural medium prevented the increase of intracellular lipids. Complexes of Lp(a) with the matrix components and antibodies increased lipid level in cultured cells. We assume that formation of large particles of desialylated Lp(a) aggregates or Lp(a)-containing complexes is a necessary step for lipid accumulation in human intimal cells.
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PMID:Effect of lipoprotein(a) on lipid metabolism of cultured human intimal aortic cells. 818 10

This study examines the role of L-selectin in monocyte adhesion to arterial endothelium, a key pathogenic event of atherosclerosis. Using a nonstatic (rotation) adhesion assay, we observed that monocyte binding to bovine aortic endothelium at 4 degrees C increased four to nine times upon endothelium activation with tumor necrosis factor (TNF)-alpha. mAb-blocking experiments demonstrated that L-selectin mediates a major part (64 +/- 18%) of monocyte attachment. Videomicroscopy experiments performed under flow indicated that monocytes abruptly halted on 8-h TNF-alpha-activated aortic endothelium, approximately 80% of monocyte attachment being mediated by L-selectin. Flow cytometric studies with a L-selectin/IgM heavy chain chimeric protein showed calcium-dependent L-selectin binding to cytokine-activated and, unexpectedly, unactivated aortic cells. Soluble L-selectin binding was completely inhibited by anti-L-selectin mAb or by aortic cell exposure to trypsin. Experiments with cycloheximide, chlorate, or neuraminidase showed that protein synthesis and sulfate groups, but not sialic acid residues, were essential for L-selectin counterreceptor function. Moreover, heparin lyases partially inhibited soluble L-selectin binding to cytokine-activated aortic cells, whereas a stronger inhibition was seen with unstimulated endothelial cells, suggesting that cytokine activation could induce the expression of additional ligand(s) for L-selectin, distinct from heparan sulfate proteoglycans. Under flow, endothelial cell treatment with heparinase inhibited by approximately 80% monocyte attachment to TNF-alpha-activated aortic endothelium, indicating a major role for heparan sulfate proteoglycans in monocyte-endothelial interactions. Thus, L-selectin mediates monocyte attachment to activated aortic endothelium, and heparan sulfate proteoglycans serve as arterial ligands for monocyte L-selectin.
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PMID:Monocyte adhesion to activated aortic endothelium: role of L-selectin and heparan sulfate proteoglycans. 904 58

Why LDL entrapped in the subendothelium should trigger events leading to chronic inflammation and to arterial wall injury is a major enigma of modern medicine. Oxidation of LDL in vitro renders the molecule potentially atherogenic, and the concept that oxidation is the major single event underlying the transformation of LDL to a proinflammatory molecule dominates the world literature. Here, an alternative hypothesis on the pathogenesis of atherosclerosis will be presented. We have found that non-oxidative, enzymatic modification of LDL with ubiquitous enzymes (protease + cholesterol esterase + neuraminidase) also transforms the molecule to an atherogenic moiety. Enzymatically altered LDL (E-LDL) shares major properties in common with lipoproteins that have been isolated from atherosclerotic lesions. It activates complement via the alternative pathway and is recognized by a scavenger receptor on human macrophages, thus inducing foam cell formation. Uptake of E-LDL is accompanied by potent induction of MCP-1 synthesis and secretion. In contrast, E-LDL does not stimulate IL-1 or TNF-production and is only a weak inducer of IL-6. Monoclonal antibodies were produced that recognize neoepitopes on E-LDL, but that do not react with native or oxidized LDL. With the use of these antibodies, extensive deposition of E-LDL in very early atherosclerotic lesions was demonstrated. Activated complement components colocalized with E-LDL, corroborating the concept that subendothelially deposited LDL is enzymatically transformed to a complement activator at the earliest stages in lesion development. The pathogenetic relevance of unhalted complement activation in atherogenesis was demonstrated with the use of C6-deficient rabbits. It was found that C6-deficiency markedly protected against development of diet-induced atherosclerosis in the experimental animals. In sum, our hypothesis departs from the mainstream of atherosclerosis research and derives from the recognition that extracellular exposition of free cholesterol in LDL-particles by itself confers pro-inflammatory properties onto the lipoprotein molecule. We believe that the degrading enzymes are ubiquitously present in the extracellular matrix, so the only requirement for atherogenesis to occur is the deposition of large amounts of LDL. Oxidative processes or infections probably play only minor roles, and reduction of LDL plasma levels will predictably represent the single most important prophylactic measure against development and progression of atherosclerosis.
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PMID:[An alternative hypothesis of the pathogenesis of atherosclerosis]. 964 97

Desialylation of low density lipoprotein (LDL) brings about accumulation of cholesterol in cultured cells. The influence of the neuraminidase-treated lipoprotein (LP) on the reverse cholesterol transport system was investigated in vitro utilizing very low density lipoprotein (VLDL), LDL, total high density lipoprotein (HDL) and its subfractions, HDL2 and HDL3, isolated from healthy donor plasma and mouse peritoneal macrophages. It was found that LP desialylation significantly: (1) decreased the capacity of total HDL and of HDL2, but not of HDL3, to efflux cellular cholesterol; (2) lowered the cholesterol esterification rate by lecithin:cholesterol acyltransferase (LCAT) without modifying the intrinsic LCAT activity of HDL; (3) increased the cholesteryl ester transfer from HDL to apo B-containing LP mediated by cholesteryl ester transfer protein (CETP); (4) enhanced the uptake by macrophages of cholesterol from HDL and LDL, although the amount of cholesterol taken up by the cells was much greater from the desialylated LDL than from desialylated HDL. Taken together, these in vitro evidences indicate that, in addition to enhancing the cell cholesterol LP uptake, desialylation may contribute to the premature development of atherosclerosis by impairing the reverse cholesterol transport system.
Atherosclerosis 1998 Jul
PMID:Lipoprotein desialylation simultaneously enhances the cell cholesterol uptake and impairs the reverse cholesterol transport system: in vitro evidences utilizing neuraminidase-treated lipoproteins and mouse peritoneal macrophages. 969 93

Sialic acid is a negatively charged sugar associated with the protein and lipid portions of lipoproteins. Sialic acid has been hypothesised to play an anti-atherogenic role in lipoprotein metabolism through the electrostatic inhibition of lipoprotein interactions with chondroitin-6-sulphate-rich arterial proteoglycans (APG). We conducted a series of studies using native and modified lipoproteins (VLDL1 Sf 60-400, VLDL2 Sf 20-60, IDL1 Sf 16-20, IDL2 Sf 12-16, LDL(A) Sf 8-12, and LDL(B) Sf0-8) that vary in their sialic acid content to examine the relationship between lipoprotein sialic acid content and its interaction with APG. Lipoprotein sialic acid was greatest in VLDL1 and decreased progressively with particle density until the IDL2 fraction (VLDL1 > VLDL2 > IDL1 > IDL2 = LDL(A) = LDL(B)). The pattern of reactivity of each fraction with APG was different from the pattern observed for lipoprotein sialic acid content (IDL2 > LDL(A) > LDL(B) > IDL1 > VLDL2 > VLDL1). Levels of sialic acid were lower in subjects with CHD as compared to control subjects but the presence of CHD had no effect on lipoprotein-APG complex formation when sex and plasma triglyceride levels were taken into account. There was also no significant relationship between the lipoprotein sialic acid content and the reactivity with APG within each lipoprotein fraction. Treatment of hypertriglyceridaemic subjects with ciprofibrate decreased lipoprotein-APG complex formation in all lipoprotein fractions. This was associated with a decrease in the total sialic acid content of apo B100-containing lipoproteins suggesting that the total sialic acid content of apo B100-containing lipoproteins has no influence on lipoprotein-APG complex formation. We next conducted in vitro experiments to manipulate LDL sialic acid content. Enzymatic removal of sialic acid from LDL with neuraminidase resulted in an increase in LDL-APG complex formation. This was accompanied by an increase in the exposure of free amino groups on LDL possibly due to disruption of interactions between free amino groups and sialic acid-containing components on LDL. Increasing LDL sialic acid content through incubation with ganglioside resulted in a decrease in lipoprotein-APG complex formation without any changes in the exposure of free amino groups on LDL. We conclude that total sialic acid content of lipoproteins is not a major determinant of their binding to APG. However, specific sialic acid-containing components on lipoproteins can affect their interaction with APG.
Atherosclerosis 1999 Aug
PMID:Sialic acid-containing components of lipoproteins influence lipoprotein-proteoglycan interactions. 1048 50

Low-density lipoprotein (LDL) concentration in plasma is an important predictor for atherosclerosis, and desialylated LDL has been proposed to be particularly atherogenic. Atherosclerosis is also associated with vascular endothelial dysfunction. We therefore wished to test the hypothesis that removal of sialic acid residues from LDL increases its ability to inhibit endothelium-dependent vasorelaxation. We studied vasorelaxant responses to acetylcholine (ACh) in isolated rabbit aortic rings as a model of endothelium-dependent relaxation, in the presence or absence of LDL treated either with saline or with neuraminidase, to cleave sialic acid residues. Vasorelaxant responses to ACh were inhibited by 300 microg protein per ml saline-treated LDL (E(max) 77.5+/-4.5 vs. 89.7+/-2.2% in the absence of LDL, P<0.05). This inhibitory effect was not altered by neuraminidase treatment of LDL. In contrast, 300 microg protein per ml LDL, either saline- or neuraminidase-treated, did not affect vasorelaxant responses to the endothelium-independent dilator sodium nitroprusside. We found no correlation between sialic acid content of saline-treated LDL and its ability to inhibit endothelium-dependent vasorelaxation, in rabbit aortic rings, at a concentration of 300 microg protein per ml. Our results therefore suggest that sialic acid content is not an important determinant of the effect of LDL on vascular endothelium-dependent relaxation.
Atherosclerosis 2001 Feb 01
PMID:Influence of sialic acid content of low-density lipoprotein particles on endothelium-dependent vasorelaxation in rabbit aorta. 1116 60


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