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)

It has been suggested previously that lipoprotein lipase may act as a ligand to enhance binding and uptake of lipoprotein particles. In the present study we have examined the capacity of bovine milk lipoprotein lipase to induce intracellular accumulation of triglyceride and cholesterol ester by VLDL (Sr 60-400) isolated from Type IV hypertriglyceridemic subject (HTg-VLDL) in HepG2 cells, independent of its lipolytic activity. We have also attempted to elucidate the cellular receptor mechanisms responsible for these effects. HTg-VLDL-mediated increases in intracellular triglyceride and cholesterol ester were dependent on the presence of an active lipase. Bovine milk lipoprotein lipase (LPL) increases triglyceride mass by 301% +/- 28% (P < 0.0005) and cholesterol ester mass by 176% +/- 12% (P < 0.0005). These HTg-VLDL-mediated increases in intracellular triglyceride and cholesterol ester did not occur when heat-inactivated lipase was used. Rhizopus lipase could replace LPL and cause equivalent increases in intracellular triglyceride and cholesterol ester (472% +/- 61%(P < 0.005) and 202% +/- 25% (P < 0.025) respectively vs. control). HTg-VLDL treated with LPL and reisolated also caused equivalent increases (274% +/- 18%(P < 0.01) and 177% +/- 12% (P < 0.005) for triglyceride and cholesterol ester). LDL also caused increases in intracellular cholesterol ester (189% +/- 20%(P < 0.005)), although three times more LDL cholesterol had to be added to achieve the same effect. These LDL-induced increases were effectively blocked by monoclonal antibodies directed against the B,E receptor binding domains of apo B (-97% +/- 13% (P < 0.0005) with anti-apo B 5E11 and -68% +/- 13% (P < 0.05) for anti-apo B B1B3) or by anti-B,E receptor antibodies (-77% +/- 7% (P < 0.01) antibody C7). These same antibodies had little effect on the HTg-VLDL+LPL-induced increases in cholesterol ester (+21%, +15% and -22% for 5E11, B1B3 and C7, respectively). Monoclonal anti-apo E antibodies also had no effect on LDL-mediated increases in intracellular cholesterol ester, but had a small and significant effect on VLDL-mediated increases in cholesterol ester. However, heparin, which interferes with cell surface proteoglycan interaction, was very effective at blocking HTg-VLDL-mediated increases in cholesterol ester in the presence of LPL (-86% +/- 8% P < 0.0005). Heparin was also effective in the presence of Rhizopus lipase (-79%) or lipolyzed re-isolated HTg-VLDL (-95%). These results suggest that lipoprotein lipase may enhance the uptake process beyond its role in lipolytic remodelling but does not appear to be an absolute requirement. In contrast, heparin had no effect on LDL-mediated cholesterol ester accumulation. Lactoferrin, which inhibits interaction with the low density lipoprotein receptor-related protein (LRP), was also very effective at inhibiting HTg-VLDL increases in intracellular cholesterol ester (-95% +/- 6%, P < 0.01). However, there was no effect of either heparin or lactoferrin on HTg-VLDL-mediated triglyceride accumulation. Thus cell surface heparin sulphate may facilitate intracellular lipid acquisition by providing a stabilizing bridge with the lipoproteins and enhance uptake through receptor-mediated processes such as LRP.
Atherosclerosis 1996 Feb
PMID:Inhibition of lipoprotein lipase induced cholesterol ester accumulation in human hepatoma HepG2 cells. 864 51

Compared to cholesterol or linoleic acid (18:2), oxidized lipids such as cholestan-3 beta, 5 alpha, 6 beta-triol (triol) and hydroperoxy linoleic acid (HPODE) markedly impair endothelial barrier function in culture [Hennig and Boissonneault, 1987; Hennig et al. 1986]. Because proteoglycans contribute to vascular permeability properties, the effects of cholesterol and 18:2 and their oxidation products, triol and HPODE, on endothelial proteoglycan metabolism were determined. While cholesterol was without effect, a concentration-dependent decrease in cellular proteoglycans (measured by 35S incorporation) was observed after exposure to triol. Compared to control cultures, cholesterol reduced mRNA levels for the proteoglycans, perlecan and biglycan. Triol had a similar effect on biglycan but not an perlecan mRNA levels. Compared to 18:2, 1,3 and 5 microM HPODE depressed cellular proteoglycans. Perlecan mRNA levels were reduced more by HPODE when compared to 18:2. Biglycan mRNA levels were reduced by 3 microM, but not by 5 microM HPODE. These data demonstrate that oxidized lipids such as triol and HPODE can decrease cellular proteoglycan metabolism in endothelial monolayers and alter mRNA levels of major specific proteoglycans in a concentration-dependent manner. This may have implications in lipid-mediated disruption of endothelial barrier function and atherosclerosis.
Atherosclerosis 1996 Feb
PMID:Oxidized lipid-mediated alterations in proteoglycan metabolism in cultured pulmonary endothelial cells. 864 61

The small leucine-rich proteoglycan biglycan is involved in several physiological and pathophysiological processes through the ability of its core protein to interact with other extracellular matrix molecules and transforming growth factor-beta (TGF-beta). To learn more about the regulation of biglycan core protein expression, we have cloned and sequenced 1218 base pairs from the 5'-flanking region of the human biglycan gene, demonstrated functional promoter activity, and investigated the molecular mechanisms through which various agents modulate its transcriptional activity. Sequencing revealed the presence of several cis-acting elements including multiple AP-2 sites and interleukin-6 response elements, a NF-kappaB site, a TGF-beta negative element, and an E-box. The TATA and CAAT box-lacking promoter possesses many features of a growth-related gene, e.g. a GC-rich immediate 5' region, many Sp1 sites, and the use of multiple transcriptional start sites. Transient transfections of the tumor cell lines MG-63, SK-UT-1, and T47D with various biglycan 5'-flanking region-luciferase reporter gene constructs showed that the proximal 78 base pairs are sufficient for full promoter activity. Several agents among them interleukin-6, and tumor necrosis factor-alpha. were capable of altering biglycan promoter activity. However, in MG-63 cells, TGF-beta1 failed to increase either activity of the biglycan promoter constructs or specific transcription from the endogenous biglycan gene. Since TGF-beta1 also did not alter the stability of cytoplasmic biglycan mRNA as determined from Northern analysis after inhibition of transcription with 5,6-dichloro-1beta-D-ribofuranosylbenzimidazole, an as yet unidentified nuclear post-transcriptional mechanism was considered responsible for the TGF-beta effect in this cell type. These results might help to elucidate the molecular pathways leading to pathological alterations of biglycan expression observed in atherosclerosis, glomerulonephritis, and fibrosis.
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PMID:Transcriptional regulation of the human biglycan gene. 866 74

The liver plays a decisive role in the regulation of the plasma levels of atherogenic lipoproteins. The primary liver interaction site for chylomicron-remnants and VLDL remnants (beta-VLDL) is still unidentified, while the subsequent cellular uptake is likely to be mediated in concert by the LDL receptor related protein (LRP) and the LDL receptor. The nature of the primary interaction site of remnants (remnant-receptor) might be a liver-specific proteoglycan or a liver-specific protein. Atherogenic modified LDL can be recognized by a family of scavenger-receptors. A newly identified 95-kDa protein forms the most likely candidate for mediating the in vivo uptake of oxidized LDL from the circulation and might thus protect the body against the presence of oxidized LDL in the blood compartment.
Atherosclerosis 1995 Dec
PMID:LDL receptor-independent and -dependent uptake of lipoproteins. 882 64

Endothelial cells interact with blood components and the abluminal tissues, thus playing an active role in many aspects of vascular function. Numerous physiologic and pathophysiologic stimuli are often mediated by nutrients that can contribute to the overall functions of endothelial cells in the regulation of vascular tone, coagulation, cellular growth, immune and inflammatory responses. Therefore, nutrient-mediated functional changes of the endothelium and the underlying tissues may be significantly involved in disease processes such as atherosclerosis. There is evidence that individual nutrients or nutrient derivatives may either provoke or prevent metabolic and physiologic perturbations of the vascular endothelium. Diets high in fat and/or calories are considered a risk factor for the development of atherosclerosis. Our research has shown that certain diet-derived lipids and their derivatives can disrupt normal endothelial integrity, thus reducing the ability of the endothelium to act as a selectively permeable barrier to blood components. Mechanisms underlying fatty acid-mediated endothelial cell dysfunction may be related to changes in fatty acid composition as well as to an increase in cellular oxidative stress. Selective lipid accumulation and fatty acid changes in endothelial cells can modulate membrane fluidity, proteoglycan metabolism and signal transduction mechanisms. Most importantly, dietary fats rich in certain unsaturated fatty acids, may be atherogenic by enhancing the formation of reactive oxygen intermediates. A subsequent imbalance in cellular oxidative stress/antioxidant status can activate oxidative stress-responsive transcription factors, which in turn may promote cytokine production, expression of adhesion molecules on the surface of endothelial cells, and thus intensify an inflammatory response in atherosclerosis. Our data also suggest that certain nutrients, which have antioxidant and/or membrane stabilizing properties, can protect endothelial cells by interfering with lipid/cytokine-mediated endothelial cell dysfunction. These findings contribute to the understanding of the interactive role of dietary fats with inflammatory components, as well as with nutrients that exhibit antiatherogenic properties, in the development of atherosclerosis.
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PMID:Nutritional implications in vascular endothelial cell metabolism. 882 90

Low density lipoprotein (LDL) is known to bind to arterial wall proteoglycans (APG), an interaction which may initiate cholesterol deposition in the arterial wall. The objective of this study was to determine whether a predominance of small, dense LDL (LDL-III, d = 1.044-1.063 g/ml) in the circulation in association with an atherogenic lipoprotein phenotype (ALP) (i.e. LDL-III > 100 mg/dl, an elevated plasma triglyceride and a low high density lipoprotein cholesterol) alters LDL reactivity towards APG. Total LDL (d = 1.019-1.063 g/ml) was isolated from 59 patients undergoing coronary angiography (39 males and 20 females) and the LDL subfraction profile determined by non-equilibrium density gradient centrifugation. A binding assay was developed in which total LDL (0.1 mg/ml apo LDL) was mixed with a standard preparation of APG containing 2.5 micrograms/ml chondroitin sulphate and the extent of APG-LDL complex formation followed by absorbance measurement and the amount of precipitated LDL cholesterol. APG-LDL complex formation was positively associated with (a) the percentage of LDL-III within total LDL (r = 0.48, P < 0.0001); (b) the plasma triglyceride level (r = 0.27, P < 0.04); and negatively associated with (a) the percentage of the buoyant LDL-I (d = 1.019-1.033 g/ml)(r = -0.47, P < 0.0001); and (b) the HDL cholesterol concentration (r = -0.37, P < 0.004). There was no association with the percentage of the major LDL species LDL-II. When the patients were divided according to the presence or absence of an ALP i.e. LDL-III greater or less than 100 mg/dl respectively, proteoglycan-LDL complex formation was significantly higher in the former compared to the latter group of patients (P < 0.0001). This study therefore provides evidence that the extent of the interaction of LDL with APG varies considerably between individuals and is enhanced in the presence of ALP. It is postulated that the increased atherogenicity associated with ALP may in part be due to prolonged and enhanced retention of LDL by the arterial wall.
Atherosclerosis 1996 Aug 02
PMID:Influence of plasma lipid and LDL-subfraction profile on the interaction between low density lipoprotein with human arterial wall proteoglycans. 883 Sep 38

Lipoprotein deposition and increased intimal proteoglycans are characteristics of the atherosclerotic lesion in which low density lipoproteins (LDL) bind with high affinity to proteoglycans. The affinity of LDL to proteoglycans is dependent on its structural and compositional characteristics. This study investigated the relationship between serum lipid levels and LDL-proteoglycan reactivity. We also analyzed how lipid-lowering drugs affect this interaction. Patients with moderate hypercholesterolemia (n = 147) were randomized to pravastatin 40 mg o.d., gemfibrozil 600 mg b.i.d., gemfibrozil+pravastatin (same doses) or placebo. LDL reactivity with proteoglycans was analyzed by precipitation of serum with isolated human arterial proteoglycans. Reactivity was determined as amount of precipitated cholesterol or apolipoprotein (apo) B. Under the conditions used, 53% of the LDL cholesterol and 29% of serum apo B were precipitated. There were strong correlations between precipitated LDL and serum levels of cholesterol, LDL or apo B. No correlations were found with serum lipoprotein(a) (Lp(a)) levels. During pravastatin treatment, cholesterol was reduced by 26.5% and triglycerides by 9.8%. During gemfibrozil treatment corresponding figures were 16.8 and 40.2, and for the combined treatment, 27.5% and 34.2%. On all treatments, the reactivity of LDL with proteoglycan was reduced. The effects were significantly larger in the groups treated with gemfibrozil. This was correlated with the increase in high density lipoprotein (HDL) during gemfibrozil treatment. In hypercholesterolemia, the reactivity of LDL with proteoglycan is increased; treatment with lipid-lowering drugs lowers this reactivity, the effect being greatest for gemfibrozil. This might be due to conformational changes of LDL during treatment with gemfibrozil, unrelated to its lipid lowering effect. Since binding of LDL to proteoglycans is central in atherogenesis, this may be of importance for the role of gemfibrozil as an antiatherogenic drug.
Atherosclerosis 1996 Jan 05
PMID:Insoluble complex formation between LDL and arterial proteoglycans in relation to serum lipid levels and effects of lipid lowering drugs. 892 56

Stimulators of angiogenesis hold potential in promoting the development of collateral circulation in ischaemic tissue and accelerating would healing, but promote pathological vasoformation in angiogenesis-dependent diseases (solid tumours, atherosclerosis). The renin-angiotensin system is implicated in both beneficial angiogenesis and pathological vascular growth. We investigated the angiogenic activity of angiotensin II (AII) in a sponge implant model in mice; this peptide enhanced angiogenesis, as well as glycosaminoglycan (GAG, chondroitin sulfate proteoglycan) and protein synthesis in sponge matrix in mice in a dose-dependent fashion. Extensive angiogenesis was achieved with AII (1 microgram), which gave no significant increase in wet weight and protein and only a small effect on GAG. In the implants treated with AII (2 micrograms) no further increase in angiogenesis was observed, whereas a marked effect was shown in wet weight (326 +/- 15 vs. 424 +/- 27 mg), total protein (18 +/- 1 vs. 25 +/- 1 micrograms/ww) and GAG (98 +/- 10 vs. 160 +/- 13 ng/ww). The local blood flow has been determined by measuring the washout rate of 133Xe injected into the implants, correlated with histological evidence of vessel growth. This model of angiogenesis has allowed sequential studies of fibrovascular tissue infiltration simultaneously with histological and biochemical parameters of angiogenesis.
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PMID:Angiotensin-II-induced angiogenesis in sponge implants in mice. 904 8

Accumulation of extracellular matrix, fibrosis, is regarded to be one of the major manifestations of atherosclerosis. Collagen type I is the predominant matrix component in human atherosclerotic plaques. In this work we have demonstrated procollagen type I expressing cells (PCI-cells) and studied their localization in grossly normal human aorta and atherosclerotic lesions: initial lesions, fatty streaks, fibrolipid lesions (fibrolipid plaque, fibroatheroma), fibrotic lesions (fibrous plaque). PCI-cells were revealed immunocytochemically using SPI.D8 monoclonal antibody against human procollagen type I. We failed to detect PCI-cells in the areas of grossly normal aorta and media underlying atherosclerotic lesions. Positively stained cells were shown in the areas of initial lesions, fatty streaks, fibrolipid and fibrous plaques. The largest amount of PCI-cells was revealed in fatty streaks. These cells were predominantly localized in the preluminal proteoglycan-rich intimal sublayer. Intimal cells in grossly normal regions formed a common cellular network contacting each other with their processes. The cellular network is found to be partly disintegrated in atherosclerotic lesions, which leads to the appearance of isolated cells. The share of isolated PCI-cells localized outside the intimal cellular network was higher in advanced lesions than in the areas of early atherosclerotic lesions. In initial lesions most of PCI-cells were identified as smooth muscle cells using antibodies to smooth muscle alpha-actin. In fatty streaks PCI-expressing smooth muscle cells were fewer in number. Much fewer cells double-stained with anti-alpha-actin and anti-PCI antibodies were found in fibrolipid and fibrous plaques. The proportion of these double stained cells was higher among total number of PCI-cells involved in the cellular network versus PCI-cells outside the network. The results of the study demonstrated that the most active de novo synthesis of interstitial collagen takes place in the regions of atherosclerotic lesions characterized by lipid deposition, which may lead to the further progression of atherosclerotic lesions.
Atherosclerosis 1997 Apr
PMID:Collagen-synthesizing cells in initial and advanced atherosclerotic lesions of human aorta. 912 57

Angiotensin II (Ang-II) has been shown to possess several atherogenic properties including its ability to induce macrophage-mediated oxidation of LDL and to form Ang-II-modified LDL which is taken up by macrophages at enhanced rate. Oxidized-LDL (Ox-LDL) is also taken up by macrophages at enhanced rate via several scavenger receptors, leading to macrophage cholesterol accumulation. In the present study we examined the effect of Ang-II on the uptake of Ox-LDL by peritoneal macrophages derived from Balb/c mice (MPM). Intraperitoneal injection of Ang-II (10(-7) M, once daily for a period of 2 days) to the mice resulted in an increased Ox-LDL uptake up to 60%, in comparison to macrophages from placebo-treated mice. Similar results were obtained when Ang-II (10(-7) M) was injected to the mice twice a week for a period of three months. This Ox-LDL uptake was Ang-II dose-dependent. The cellular uptake of acetylated-LDL (Ac-LDL), another ligand for scavenger receptors, however, was not affected by Ang-II injection to the mice. Furthermore, preincubation of the MPM with the monoclonal antibody, anti CD36, reduced macrophage uptake of Ox-LDL in Ang-II-treated mice by only 11%. Ang-II administration to mice resulted in a 60% increase in the macrophage cellular proteoglycan content. Chondroitinase treatment of MPM decreased Ox-LDL cellular uptake by 20% and by 38% in placebo-treated and Ang-II-treated cells, respectively. We thus conclude that Ang-II administration to mice enhances their macrophage Ox-LDL uptake via its stimulating effect on cellular proteoglycan content and this process can lead to foam cell formation and atherosclerosis.
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PMID:Angiotensin II injection into mice increases the uptake of oxidized LDL by their macrophages via a proteoglycan-mediated pathway. 934 70


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