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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Deposition of cholesterol esters in the arterial intima is a characteristic feature of human atherosclerosis. Very little is known about the mechanisms by which cells normally regulate their cholesterol ester content. Recent studies in cultured human cells demonstrate the existence of a cell surface receptor that binds plasma low density lipoproteins and regulates the sterol content of cells by modulating the rates of uptake, esterification, and synthesis of cholesterol. A possible role for this lipoprotein receptor in the pathogenesis of atherosclerosis is discussed.
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PMID:Lipoprotein receptors, cholesterol metabolism, and atherosclerosis. 16 32

The studies reported here, coupled with our previous studies, indicate that LDL is ingested by cultured human fibroblasts in a process that resembles adsorptive endocytosis. The critical step is the binding of the lipoprotein to a high-affinity cell surface receptor. Uptake of LDL by this receptor-mediated process permits the cell to aquire cholesterol from the lipoprotein, and this acquisition, in turn, suppresses the cell's own cholesterol synthesis and activates the cell's system for reesterification and storage of the incoming cholesterol. In cells from patients with the receptor-negative form of homozygous FH, the cell surface receptor is functionally absent. The absence of high-affinity binding to this receptor produces a defective uptake of LDL and prevents the normal process of feedback regulation of cholesterol synthesis by the lipoprotein. The physiologic importance of the LDL pathway is indicated by the fact that patients who lack the LDL receptor (FH homozygotes) develop both profound hyper-cholesterolemia and fulminant atherosclerosis. It is likely that other defects in the LDL pathway account for other forms of hypercholesterolemia and atherosclerosis in man.
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PMID:The low-density lipoprotein pathway in human fibroblasts: relation between cell surface receptor binding and endocytosis of low-density lipoprotein. 18 67

Previous studies have shown that calcium-antagonists may reduce the development of experimental atherosclerosis, and that nifedipine may slow progression of coronary atherosclerosis in man. The mechanisms responsible for this effect are still unclear. It has been recently proposed that oxygen-free radicals can induce peroxidation of human low-density lipoproteins (LDL), and that peroxidized LDL may be an atherogenic stimulus. Chemical modified LDL are internalized by macrophages via specific cell surface receptor that was termed the scavenger receptor, and could induce foam cells transformation in vivo. Previous studies on other systems have shown that calcium-antagonists may effectively inhibit oxygen radical-induced lipid peroxidation. These drugs, though differing widely in their chemical structure, are lipophilic to various degrees and presumably would concentrate in the lipid domain of the phospholipid-rich membranes. Therefore, the aim of the present study was to investigate whether calcium-channel blockers may reduce human LDL peroxidation. Purified human LDL were exposed to oxygen radicals generated by xanthine-xanthine oxidase (18 hours) after a pre-incubation (30 min) in presence of different concentrations of nifedipine, diltiazem and verapamil. Peroxidation was measured from malonyldialdehyde production. The results show that calcium-antagonists prevent LDL peroxidation. Thus, calcium-antagonists may reduce peroxidation of human LDL in vitro, at clinically relevant concentrations. These data suggest that reduced formation of atherogenic peroxidized LDL may be an additional mechanism for the anti-atherosclerotic effects of calcium-antagonists in vivo.
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PMID:[Calcium channel blockers inhibit human low-density lipoprotein peroxidation induced by oxygen free radicals in vitro]. 129 53

The control of vascular endothelial and smooth muscle cell proliferation is important in such processes as tumor angiogenesis, wound healing, and the pathogenesis of atherosclerosis. Class I heparin-binding growth factor (HBGF-I) is a potent mitogen and chemoattractant for human endothelial cells in vitro and will induce angiogenesis in vivo. RNA gel blot hybridization experiments demonstrate that cultured human vascular smooth muscle cells, but not human umbilical vein endothelial cells, express HBGF-I mRNA. Smooth muscle cells also synthesize an HBGF-I-like polypeptide since (i) extract prepared from smooth muscle cells will compete with 125I-labeled HBGF-I for binding to the HBGF-I cell surface receptor, and (ii) the competing ligand is eluted from heparin-Sepharose affinity resin at a NaCl concentration similar to that required by purified bovine brain HBGF-I and stimulates endothelial cell proliferation in vitro. Furthermore, like endothelial cells, smooth muscle cells possess cell-surface-associated HBGF-I receptors and respond to HBGF-I as a mitogen. These results indicate the potential for an additional autocrine component of vascular smooth muscle cell growth control and establish a vessel wall source of HBGF-I for endothelial cell division in vivo.
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PMID:Human vascular smooth muscle cells both express and respond to heparin-binding growth factor I (endothelial cell growth factor). 244 75

Uptake of cholesterol-containing lipoproteins by macrophages in the arterial intima is believed to be an important step in the pathogenesis of atherosclerosis. There are a number of possible mechanisms by which macrophages might accumulate cholesterol, and one that has attracted much interest recently involves the uptake of oxidatively modified low density lipoprotein (LDL) via a specific cell surface receptor, termed the scavenger or acetyl-LDL receptor. Previous studies have shown that chemical derivatization of LDL with reagents that result in neutralization of the charge of lysine amino groups also allows recognition by this receptor. As well, it has been shown that oxidation of LDL is accompanied by a decrease in free lysine groups and binding of lipid products to apolipoprotein B. The present studies were done to further characterize the receptor-binding domain on oxidized LDL. It was found that LDL could be modified by incubation with water-soluble products derived from autoxidized unsaturated fatty acids under conditions that inhibited oxidation of the LDL itself. The LDL modified in this way had increased electrophoretic mobility but showed no evidence of the oxidative damage that typifies LDL oxidized by exposure to metal ions. Furthermore, the oxidation product-modified LDL was rapidly degraded by cultured macrophages through the scavenger receptor pathway. Bovine albumin modified by oxidation products also showed greatly accelerated degradation by macrophages. When analyzed by reverse-phase high pressure liquid chromatography, the reactive oxidation products appeared less polar than fatty acids or simple medium-chain aldehydes. When treated with the carbonyl reagent 2,4-dinitrophenylhydrazine, the reactive fractions yielded derivatives, some of which were identified by mass spectrometry as hydrazones of nonenal, heptenal, pentenal, and crotonaldehyde. A series of 2-unsaturated aldehydes (acrolein to 2-nonenal) were all found to modify LDL, but none of these aldehyde-modified LDLs were recognized by the scavenger receptor of macrophages and all were degraded much more slowly by these cells than LDL modified with oxidation products. Furthermore, copper-oxidized LDL had only very slight immunoreactivity toward a panel of antibodies specific for adducts of simple 2-unsaturated aldehydes. Analysis of underivatized autoxidized fatty acids by coupled liquid chromatography/thermospray mass spectrometry revealed compounds with m/z corresponding to M+17, M+31, and 2M+31 in fractions that were capable of modifying LDL. The unoxidized fatty acids showed a dominant peak at M-1. These results indicate that the scavenger receptor of macrophages can recogn
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PMID:Recognition of oxidized low density lipoprotein by the scavenger receptor of macrophages results from derivatization of apolipoprotein B by products of fatty acid peroxidation. 276 57

The effect of hydrocortisone on the cellular low density lipoprotein (LDL) pathway was studied in cultured human skin fibroblasts and arterial smooth muscle cells. Hydrocortisone decreased both uptake and degradation of 125I-LDL, LDL binding, measured at 4 C, was not affected by the hormone. Physiological concentrations of hydrocortisone (4 . 1 X 10(-8) mol/l) resulted in a 30% reduction of LDL uptake and degradation which could not be accounted for by an effect of the hormone on macromolecular synthesis, cell protein or cell number. To test whether the decrease in uptake and degradation of 125I-LDL was due to reduced internalization, the effect of hydrocortisone on the internalization of prebound LDL was determined and found to be decreased. Also, preincubation with unlabelled LDL in the presence of hydrocortisone resulted in less down regulation of LDL receptor activity than when no hydrocortisone was present. An effect of the hormone on bulk phase endocytosis has been excluded, since hydrocortisone did not affect either LDL degradation by receptor negative cells or endocytosis of 14C-sucrose by normal skin fibroblasts. Thus, hydrocortisone impairs LDL catabolism by decreasing the internalization of LDL normally bound to its cell surface receptor. These results may be relevant to the pathogenesis of atherosclerosis in conditions associated with reduced cellular LDL catabolism.
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PMID:Hydrocortisone decreases the internalization of low density lipoprotein in cultured human fibroblasts and arterial smooth muscle cells. 619 93

The procoagulant response of endothelium to pathophysiological agents such as tumour necrosis factor alpha (TNF alpha) and phorbol myristate acetate (PMA) alters the expression of proteins such as tissue factor. The modulation of such procoagulant activity (PCA) by the polyunsaturated fatty acid arachidonic acid (20:4,n-6) and its 15-hydroperoxy (15-HPETE) and 15-hydroxy (15-HETE) metabolites was examined since this may have important implications in cardiovascular disease and atherosclerosis. Treatment of human umbilical vein endothelial cells (HUVEC) for 30 min with 20:4, 15-HPETE or 15-HETE before induction of PCA with TNF alpha (100 U) or PMA (10(-7) M) caused a significant inhibition of PCA. This inhibition was seen at 2-5 microM fatty acids. Dose response curves with TNF alpha indicated that the inhibition was greatest at higher concentrations of TNF alpha (> or = 250U TNF alpha/ml). The mode of administration of the fatty acid was not critical as fatty acids presented as DPC-fatty acid micelles or solubilised in ethanol gave similar inhibitions of PCA. 20:4, 15-HPETE or 15-HETE did not alter the binding of I125-labelled TNF alpha to its surface receptors on HUVEC, suggesting that the effect of these fatty acids was not mediated by events at the cell surface receptor level. In support of this, these fatty acids were found to inhibit PCA induced by PMA which bypasses cell surface receptors to activate protein kinase C directly.(ABSTRACT TRUNCATED AT 250 WORDS)
Atherosclerosis 1995 Jul
PMID:Inhibitory effects of arachidonic acid (20:4,n-6) and its monohydroperoxy- and hydroxy-metabolites on procoagulant activity in endothelial cells. 748 27

Heparin and heparin-like molecules may function, apart from their effect on hemostasis, as regulators of cell growth and neovascularization. We investigated whether similar effects are exerted by laminarin sulfate, an unrelated polysulfated saccharide isolated from the cell wall of seaweed and composed of chemically O-sulfated beta-(1,3)-linked glucose residues. Laminarin sulfate exhibits about 30% of the anticoagulant activity of heparin and is effective therapeutically in the prevention and treatment of cerebrovascular diseases. We characterized the effect of laminarin sulfate on interaction of the heparin-binding angiogenic factor, basic fibroblast growth factor (bFGF), with a naturally produced subendothelial extra-cellular matrix (ECM) and with cell surface receptor sites. Laminarin sulfate (1-2 micrograms/ml) inhibited the binding of bFGF to ECM and to the surface of vascular smooth muscle cells (SMC) in a manner similar to that observed with heparin. Likewise, laminarin sulfate efficiently displaced both ECM- and cell-bound bFGF at concentrations as low as 1 microgram/ml. Both laminarin sulfate and heparin efficiently induced restoration of bFGF receptor binding in xylosyltransferase-deficient CHO cell mutants defective in initiation of glycosaminoglycan synthesis. Moreover, laminarin sulfate elicited bFGF receptor activation and mitogenic response in heparan sulfate (HS)-deficient, cytokine-dependent lymphoid cells. These results indicate that laminarin sulfate effectively replaced the need for heparin and HS in the induction of bFGF receptor binding and signaling. In other experiments, laminarin sulfate was found to inhibit the proliferation of vascular SMC in a manner similar to that observed with heparin. These effects of laminarin sulfate may have potential clinical applications in diverse situations such as wound healing, angiogenesis, and atherosclerosis.
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PMID:Laminarin sulfate mimics the effects of heparin on smooth muscle cell proliferation and basic fibroblast growth factor-receptor binding and mitogenic activity. 765 58

Low-density lipoproteins (LDL) oxidized by oxygen radicals are a potent atherogenic stimulus. Chemically modified LDL are internalized by macrophages via a specific cell surface receptor that was termed the scavenger receptor, and could induce foam cell transformation. Post-translational nonenzymatic glycosylation of low density lipoprotein (LDL) occurs in vivo in diabetic patients. Glycosylated LDL (glcLDL) is degraded by macrophages in part by the classic LDL-receptor and in part by the scavenger receptor. This latter mechanism may contribute to the formation of foam cells and acceleration of atherosclerosis in diabetes mellitus. Oxygen free radicals (ORs) could induce LDL peroxidation and subsequent formation of foam cells. Glycosylation may alter protein conformation. A free radical is any chemical species that has an unpaired electron. This property renders it highly chemically reactive. When a radical reacts with a non radical another free radical is generated. This characteristic enables radicals to trigger chain reactions. Oxygen radicals are: superoxide anion (.O2-), hydroxyl radical (.OH) and hydrogen peroxide (H2O2). Thus, the aim of this study was to investigate whether glcLDL are susceptible to peroxidative modification by ORs. GlcLDL was prepared incubating LDL with 40 mM glucose in sterile phosphate-buffer-EDTA 1 mM for 10 days at 37 degrees C. Control LDL (cLDL) was similarly incubated with buffer but without glucose. After this preparation both forms of LDL were oxidized by CuSO4 (15 microM for 20 hours at 37 degrees C) or by xanthine/xanthine oxidase (X:2 mM/XO: 100 mU for 20 hours at 37 degrees C).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[The peroxidation of human glycosylated low-density lipoproteins is mediated by the superoxide radical: the protective effects of superoxide dismutase]. 808 16

The phenotypic transition of smooth muscle cells (SMC) from a contractile to a synthetic state appears to be an early event in the pathogenesis of atherosclerosis. We examined the effects of extracellular matrix components on the phenotypic modulation of rabbit arterial SMC in primary culture by flow cytometry. The results demonstrate that freshly isolated SMC attached, spread, and started to proliferate on type I collagen as well as on fibronectin. Moreover, type I collagen was as efficient as fibronectin in promoting the transition of the cells into the synthetic phenotype without exogenous mitogens. However, unlike on fibronectin, the synthetic peptide GRGDSP (Gly-Arg-Gly-Asp-Ser-Pro) and the peptide KDGEA (Lys-Asp-Gly-Glu-Ala), which contains the recognition sequence for alpha 2 beta 1 integrin in type I collagen, interfered little with the attachment, spreading, and phenotypic modulation of the cells on type I collagen. On the other hand, the phenotypic modulation of the cells was counteracted by the anti-beta 1 integrin antibody. These findings indicate that type I collagen promotes the phenotypic transition of the rabbit arterial SMC by interacting with a cell surface receptor (beta 1 integrin family) for a cell-binding sequence without RGD and DGEA. In contrast, elastin, a major constituent of the media, suppressed the cell attachment and spreading and maintained the cells in the contractile phenotype as laminin. These results suggest diverse roles of type I collagen and elastin as well as of fibronectin and laminin in the control of the differentiated properties of arterial SMC.
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PMID:Type I collagen promotes modulation of cultured rabbit arterial smooth muscle cells from a contractile to a synthetic phenotype. 841 90


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