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)

This report describes the enhancement of growth potentiating activity produced by mononuclear phagocytes that were incubated with beta-migrating very low density lipoproteins (beta-VLDL). Conditioned media harvested from cultured human peripheral blood monocytes incubated in the presence or absence of the lipoprotein were evaluated for their ability to stimulate DNA synthesis ([3H]thymidine incorporation) of sparsely seeded quiescent BHK-21 (BHK) cells as well as neonatal rat aortic smooth muscle cells (NRSMC). Conditioned media from monocytes incubated in the presence of beta-VLDL enhanced [3H]thymidine incorporation into DNA of both BHK and NRSMC, when compared to conditioned media harvested from monocytes incubated in the absence of beta-VLDL. Studying NRSMC, this effect was evident using media collected from monocytes incubated with lipoprotein for 2 days; however, a longer incubation of monocytes plus lipoprotein was necessary to induce changes in growth potentiating activity for BHK cells. Likewise, the effect of beta-VLDL treatment of thioglycollate broth elicited BALB/c mouse peritoneal macrophages was evaluated. Conditioned media from lipoprotein-treated macrophages exhibited greater growth-stimulating activity for both BHK cells and NRSMC when compared to conditioned media from macrophages incubated in the absence of the lipoprotein. beta-VLDL did not affect viability of the mononuclear cells. These findings further implicate the involvement of the monocyte-derived foam cell in the development of atherosclerosis.
Atherosclerosis 1988 Jan
PMID:beta-VLDL-induced alterations in growth potentiating activity produced by mononuclear phagocytes. 335 8

The presence of specific receptors for the metabolism of acetylated low density lipoprotein (AcLDL) and beta-migrating very low density lipoprotein (beta-VLDL) was demonstrated in thioglycolate-elicited peritoneal macrophages from both atherosclerosis-susceptible White Carneau (WC) and resistant Show Racer (SR) pigeons. Macrophages from both breeds metabolized AcLDL through a single class of receptors that were similar, but not identical, to the scavenger receptors described in mammalian macrophages. Both pigeon and mammalian AcLDL bound to this receptor. At 37 degrees C, AcLDL was internalized and degraded in the lysosomes, and cholesterol esterification and cholesteryl ester accumulation were stimulated. As in mammalian macrophages, AcLDL receptor activity was not down-regulated by cholesterol loading. In contrast, AcLDL binding was poorly competed for by fucoidin or polyinosinic acid, and the magnitude of cholesteryl ester accumulation was only about one-half of that seen with mouse peritoneal macrophages. Pigeon beta-VLDL bound to both a high and a low affinity site on pigeon macrophages. Binding to the high affinity site was calcium-dependent, pronase-sensitive, and down-regulated by cholesterol loading. Cholesterol esterification and cholesteryl ester accumulation with beta-VLDL were stimulated to an equal or greater extent than with AcLDL. Unlike mammalian macrophages, the pigeon beta-VLDL receptor did not require apolipoprotein E, as evidenced by the lack of apoE in pigeon lipoproteins and by the failure of rabbit beta-VLDL, containing apoE, to compete for binding. Pigeon LDL, but not mammalian LDL, was recognized by the pigeon beta-VLDL receptor, suggesting that like the mammalian beta-VLDL receptor, the pigeon beta-VLDL receptor may be a form of an LDL receptor. This was an unexpected finding since pigeon fibroblasts and smooth muscle cells in culture do not express LDL receptors. Thus, pigeon macrophages have receptors for the uptake of abnormal lipoproteins that could play a role in the development of macrophage-derived foam cells that are prevalent in the early stages of atherosclerosis in this species. No quantitative or qualitative differences in these receptors, however, were identified that could account for the differences in atherosclerosis susceptibility between the WC and SR breeds.
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PMID:Lipoprotein metabolism by macrophages from atherosclerosis-susceptible White Carneau and resistant Show Racer pigeons. 341 Dec 39

The lipid-laden foam cells from atherosclerotic lesions appear to be derived from macrophages which have accumulated lipids from plasma lipoproteins. When examined in vitro, thioglycolate-elicited mouse peritoneal macrophages do not accumulate lipids when exposed to normal low density lipoproteins (LDL), but take up very low density lipoproteins (VLDL) or chemically modified LDL with resultant lipid accumulation. Patients with noninsulin-dependent diabetes mellitus (NIDDM) have an increased incidence of atherosclerosis, due in part to disturbances in lipoprotein metabolism. We investigated the possibility that VLDL isolated from patients with NIDDM are taken up by mouse peritoneal macrophages more avidly than normal. Two groups of patients with NIDDM were studied; one group was normotriglyceridemic and the other group was hypertriglyceridemic. The VLDL from both normotriglyceridemic and hypertriglyceridemic patients were enriched in cholesterol and triglyceride compared to that from normal subjects. Thioglycolate-elicited mouse peritoneal macrophages bound and degraded greater amounts of VLDL isolated from patients with NIDDM (both normo- and hypertriglyceridemic) than of VLDL from normal subjects. While normal VLDL caused a marked increase in cellular triglyceride and cholesteryl ester contents in macrophages, VLDL isolated from patients with NIDDM resulted in an even greater cellular accumulation of lipids. These results suggest that the VLDL of patients with NIDDM have alterations in their composition and metabolic behavior. The increased uptake of VLDL by macrophages may contribute to the enhanced atherosclerosis present in NIDDM.
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PMID:Effects of noninsulin-dependent diabetes mellitus on the uptake of very low density lipoproteins by thioglycolate-elicited mouse peritoneal macrophages. 400 10

The uptake of oxidized low density lipoprotein (ox-LDL) by macrophages and the resulting accumulation of low density lipoprotein (LDL) lipids within the cells has been implicated in the pathogenesis of atherosclerosis. The effect of fibronectin (FN) on the binding and uptake of ox-LDL by macrophages was investigated using thioglycollate-induced mouse peritoneal macrophages. The ability of the macrophages to bind ox-LDL was assessed by the binding of mouse red blood cells (RBC) pre-coated with ox-LDL (ox-LDL-RBC) prepared in vitro to macrophages at 37 degrees C. The binding of ox-LDL-RBC to macrophages was significantly enhanced when the macrophages were plated on a FN-coated substrate. Similar enhancement was observed when the macrophages were plated on a substrate pre-coated with Gly-Arg-Gly-Asp-Ser-Pro (GRGDSP) peptide, an adhesive sequence of FN involved in binding to the cells, but not with the control Gly-Arg-Gly-Glu-Ser-Pro (GRGESP) peptide. The effect of FN was inhibited when GRGDSP, but not GRGESP, was present during the macrophage attachment to the FN-coated substrate, suggesting that the specific interaction of this sequence and the FN-receptor is responsible for the effect of FN. The addition of FN or GRGDSP in solution to the macrophage layers on an uncoated substrate was ineffective. Thus, attachment to a substrate is necessary for FN to be effective on the macrophages.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Binding and uptake of oxidized low density lipoprotein (LDL) by macrophage scavenger receptors are enhanced by substrate-bound fibronectin. 755 Jan 11

The chemotactic cytokine, monocyte chemoattractant protein-1 (MCP-1), and its murine homologue, JE, have been detected in atherosclerotic lesions but not in normal arteries, implicating that these proinflammatory cytokines may be involved in the pathogenesis of atherosclerosis. Epidemiologic studies reveal that postmenopausal women receiving estrogen replacement for treatment of osteoporosis have a greatly reduced risk of developing cardiovascular disease. Because JE/MCP-1 and estrogen play regulatory roles in the development of atherosclerotic lesions, we chose to examine the effect of estrogen treatment on JE/MCP-1 mRNA expression in macrophages. 17 beta-estradiol (E2) inhibited LPS-stimulated JE/MCP-1 mRNA expression in ANA-1 and J774A.1 murine macrophage cell lines and in thioglycolate-elicited murine peritoneal macrophages. Inhibition of JE/MCP-1 mRNA ranged from 50 to 90%, with a maximal effect occurring at a concentration of 300 pg/ml E2. Conversely, E2 had little effect on LPS-stimulated TNF-alpha mRNA production. Treatment of LPS-stimulated macrophages with moxestrol, an estrogen agonist, resulted in a similar inhibition, and the addition of the estrogen antagonist, tamoxifen, reversed E2 inhibition of JE/MCP-1 mRNA expression. Progesterone failed to inhibit LPS-induced JE/MCP-1 mRNA expression. Immunohistochemical analysis revealed the presence of estrogen receptors in ANA-1 cells, indicating that E2 inhibition of LPS-induced JE/MCP-1 mRNA expression in murine macrophages may be mediated through the estrogen receptor. Thus, another mechanism whereby estrogen exerts antiatherogenic effects may be through prevention of macrophage accumulation in the atherosclerotic lesion.
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PMID:Estrogen modulation of JE/monocyte chemoattractant protein-1 mRNA expression in murine macrophages. 783 68

Abdominal aortic aneurysms are characterized by intimal atherosclerosis, disruption and attenuation of the elastic media, and a variable adventitial inflammatory infiltrate. We have developed an animal model of this disorder to evaluate the contribution of hypercholesterolemia, medial injury, and adventitial inflammation to aneurysmal dilatation. To accomplish this, we used periaortic application of calcium chloride, which induced both medial injury with calcification and endothelial injury. Ultrasonography was used to demonstrate the dilatation and thickening of the aortic wall. Over the first 3 weeks after periaortic application of 0.25 mol/L CaCl2, the external aortic diameter increased from 3.5 +/- 0.5 to 4.2 +/- 0.8 mm, but the ID remained unchanged. This apparent wall thickening was accompanied by vascular remodeling, and biochemical changes included approximately 50% reduction in tissue hydroxyproline concentration and increased activity of gelatinases (matrix metalloproteinase [MMP]-2 and MMP-9). Independently, cholesterol feeding to induce hypercholesterolemia or the concomitant periaortic application of thioglycollate had little effect on the histological, biochemical, or diameter changes. Together, hypercholesterolemia and thioglycollate were associated with rapid aortic dilatation in CaCl2, treated animals but not controls: after 3 weeks, the ID and OD had doubled, the OD increasing from 3.5 +/- 0.4 to 7.1 +/- 0.4 mm, P = .005. The remarkable feature that accompanied this dilatation was the infiltration of cells, mostly foamy macrophages, into the adventitia, with a further reduction in hydroxyproline concentration. Adventitial inflammation may provide the critical stimulus to dilatation of an aorta with preexisting intimal and medial injury.
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PMID:Influence of hypercholesterolemia and adventitial inflammation on the development of aortic aneurysm in rabbits. 901 31

The feeding of cholesterol-enriched diet for 2 weeks was enough to reduce nitric oxide (NO), prostaglandin E(2) (PGE(2) and interleukin-1 (IL-1) productions in thioglycollate-elicited murine macrophages. Although not showing anti-hypercholesterolemic action against ICR mice, Shosaikoto, a Kampo medicine, partially prevented the reduction of NO and IL-1 productions induced by the feeding of cholesterol-enriched diet, and completely released the reduction of PGE(2) production. These data suggest that the malfunction of macrophage induced by hypercholesterolemia may contribute to early atherogenesis and that Shosaikoto retains macrophage function to prevent the development of atherosclerosis, even though serum cholesterol is markedly increased.
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PMID:Shosaikoto (kampo medicine) protects macrophage function from suppression by hypercholesterolemia. 913 79

Oxidation of low density lipoproteins (LDL) has been implicated as a causal factor in the pathogenesis of atherosclerosis. Oxidized LDL has been found to exhibit numerous potentially atherogenic properties in vitro, including receptor-mediated uptake by macrophages. Oxidized LDL is a ligand for the class A scavenger receptor type I/II (SR-AI/II), but cross-competition studies with cultured macrophages suggested that there is an additional receptor(s) that is specific for oxidized LDL and that does not interact with acetyl LDL or other chemically modified LDL. A number of macrophage membrane proteins, including CD36, FcgammaRII-B2, scavenger receptor BI, and macrosialin/CD68, have been found to bind to oxidized LDL in vitro and have been proposed as candidate oxidized LDL receptors. However, because of overlapping ligand specificity with the SR-AI/II, it has been difficult to evaluate the relative importance of these proteins in the uptake of oxidized LDL by macrophages. In the present report, we have studied the uptake and degradation of oxidized LDL by macrophages from mice in which the SR-AI/II gene had been disrupted. The uptake of acetyl LDL was reduced by more than 80% in macrophages from scavenger receptor knockout mice, confirming that most of the uptake of acetyl LDL by macrophages can be attributed to this receptor. In contrast, the uptake of extensively oxidized LDL was reduced by only 30% and showed high affinity, saturable uptake with apparent Km of about 5 microg/ml, similar to that of the SR-AI/II. This indicates that about 70% of the uptake of oxidized LDL in macrophages is attributable to an alternate oxidized LDL receptor(s). In contrast to findings reported with CD36, mildly oxidized LDL was internalized much more slowly than extensively oxidized LDL. Unlabeled oxidized LDL, polyinosinic acid, phosphatidylserine-rich liposomes, and LDL or bovine albumin modified by fatty acid oxidation products were effective competitors for the uptake of radioiodinated oxidized LDL by macrophages from knockout mice, whereas acetyl LDL and malondialdehyde-modified LDL were relatively poor competitors. This ligand specificity differs from that of CD36-related (class B) scavenger receptors but is similar to the reported specificity of macrosialin/CD68 in ligand blots. However, the rate of uptake of oxidized LDL by knockout macrophages was not increased by phorbol ester or in thioglycollate-elicited macrophages, both of which are expected to increase the amount of macrosialin on the cell surface. In macrophages from SR-AI/II knockout mice, ligand blots of membrane proteins with iodinated, oxidized, or acetylated LDL revealed several bands, with apparent molecular size on SDS-polyacrylamide gel electrophoresis of 60, 94, 124, and 210 kDa, but none of the bands were specific for oxidized LDL. These results provide direct evidence that a receptor other than SR-AI/II is responsible for most of the uptake of oxidized LDL in murine macrophages, but further studies are needed to identify the receptor(s) involved.
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PMID:High affinity saturable uptake of oxidized low density lipoprotein by macrophages from mice lacking the scavenger receptor class A type I/II. 914 99

Monocyte chemoattractant protein-1 (MCP-1) is a potent agonist for mononuclear leukocytes and has been implicated in the pathogenesis of atherosclerosis and granulomatous lung disease. To determine the role of MCP-1 and related family members in vivo, we used homologous recombination in embryonic stem cells to generate mice with a targeted disruption of C-C chemokine receptor 2 (CCR2), the receptor for MCP-1. CCR2-/- mice were born at the expected Mendelian ratios and developed normally. In response to thioglycollate, the recruitment of peritoneal macrophages decreased selectively. In in vitro chemotaxis assays, CCR2-/- leukocytes failed to migrate in response to MCP-1. Granulomatous lung disease was induced in presensitized mice by embolization with beads coupled to purified protein derivative (PPD) of Mycobacterium bovis. As compared with wild-type littermates, CCR2-/- mice had a decrease in granuloma size accompanied by a dramatic decrease in the level of interferon gamma in the draining lymph nodes. Production of interferon gamma was also decreased in PPD-sensitized splenocytes from CCR2-/- mice and in naive splenocytes activated by concanavalin A. We conclude that CCR2-/- mice have significant defects in both delayed-type hypersensitivity responses and production of Th1-type cytokines. These data suggest an important and unexpected role for CCR2 activation in modulating the immune response, as well as in recruiting monocytes/macrophages to sites of inflammation.
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PMID:Impaired monocyte migration and reduced type 1 (Th1) cytokine responses in C-C chemokine receptor 2 knockout mice. 936 70

Macrophages/foam cells have a pivotal role in atherogenesis although little is known about the way lipid imbalance, a hallmark of atherosclerosis, leads to lipid accumulation in these cells. Modified low-density lipoproteins are associated with macrophage lipid dysfunction in atherosclerosis, but a possible role for altered lipogenesis leading to lipid accumulation remains to be elucidated. Since endothelium-derived nitric oxide (NO) and prostaglandins (PGs) are physiological autacoids whose production may be impaired in atherosclerosis, the effects of these mediators on de novo lipid synthesis in 24-h cultured rat peritoneal macrophages is investigated. In resident (unstimulated) cells, 1 microM PGE2 and the stable analog of PGI2 carbaprostacyclin (cPGI2, 1 microM) deviated the overall [1-14C]acetate from incorporation into cholesterol, free fatty acids and triacylglycerols favoring the formation of phospholipids. In inflammatory (thioglycollate-elicited) macrophages, these eicosanoids likewise reduced 14C-incorporations into all the lipid fractions tested. Also, cPGI2 and PGE2 reduced [4-14C]cholesterol uptake from inflammatory cells but did not interfere in 14C-cholesterol export. The PGE2-derivative PGA2 (10-20 microM) reduced 14C-incorporations into all the lipids in resident cells while it enhanced phospholipid synthesis by up to 129% at the expense of reduced incorporations into the other test lipids. The NO donor S-nitroso-N-acetylpenicillamine (SNAP, 1-10 microM), when added to macrophages in the presence of superoxide dismutase (SOD, to avoid the reaction of superoxide with NO), significantly reduced lipogenesis especially in inflammatory cells. These findings suggest that endothelium-derived NO and PGs may be associated with macrophage lipid accumulation by modulating lipogenesis and cholesterol uptake within these cells.
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PMID:Effects of prostaglandins and nitric oxide on rat macrophage lipid metabolism in culture: implications for arterial wall-leukocyte interplay in atherosclerosis. 986 55


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