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

The ability of macrophages to influence the metabolism of native low density lipoprotein by arterial smooth muscle cells was evaluated using cultured human monocyte-derived macrophages. Macrophage-conditioned medium stimulated the binding and degradation of low density lipoprotein by cultured arterial smooth muscle cells and skin fibroblasts. Sterol synthesis also was stimulated by macrophage-conditioned medium as was cholesterol esterification in the presence of high concentrations of low density lipoprotein. These findings suggest that macrophages secrete a factor that enhances the activity of the low density lipoprotein receptor. Low density lipoprotein degradation by arterial smooth muscle cells also was enhanced by macrophage-conditioned medium in the presence of high concentrations of low density lipoproteins in the medium. The macrophage factor that stimulates low density lipoprotein metabolism is stable to freezing, is inactivated by acid hydrolysis, tryptic digestion, and boiling, and is of large molecular weight (greater than 12,000 to 14,000 daltons). Modulation of arterial smooth muscle cell metabolism of low density lipoprotein by a macrophage secretory product may be of importance in the pathogenesis of atherosclerosis.
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PMID:A secretory product of human monocyte-derived macrophages stimulates low density lipoprotein receptor activity in arterial smooth muscle cells and skin fibroblasts. 627 62

Patients with familial hypercholesterolemia have elevated levels of plasma low density lipoproteins (LDL), increased hepatic synthesis of apolipoprotein B-containing lipoproteins, defective binding of low density lipoproteins to fibroblasts, and premature atherosclerosis. The role of a hepatic low density lipoprotein receptor in normal man and its importance in the pathogenesis of familial hypercholesterolemia have not been previously determined. In the present study, direct comparison was made of the binding of LDL to hepatic membranes from normal and receptor-negative homozygous familial hypercholesterolemic subjects. The effects of calcium, EDTA, and temperature on the binding of lipoproteins to the hepatic membranes were also evaluated. At 4 degrees C, no significant difference in specific binding of LDL to hepatic membranes from normal and familial hypercholesterolemic subjects was observed. At 37 degrees C, both total and specific binding of LDL were significantly reduced in patients with familial hypercholesterolemia. Hepatic membrane binding of LDL from the two patients homozygous for receptor-negative familial hypercholesterolemia was 53 and 59% of normal. The activity of the rate-limiting enzyme in cholesterol biosynthesis, 3-hydroxy-3-methylglutaryl coenzyme A reductase was normal; however, the total hepatic cholesterol and cholesteryl ester content was significantly increased from 53 to 129%. These results indicate that patients with familial hypercholesterolemia have a defect in the interaction of hepatic membranes with low density lipoproteins. This defect may lead to accelerated atherosclerosis by decreasing the cellular catabolism of LDL and enhancing the production of LDL, which is characteristic of patients homozygous for familial hypercholesterolemia.
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PMID:Characterization of hepatic low density lipoprotein binding and cholesterol metabolism in normal and homozygous familial hypercholesterolemic subjects. 632 55

The function of the low density lipoprotein receptor has been reviewed at the cell level and in man. Its key role in cholesterol metabolism is unquestioned and it is central to the actions of a number of important hypocholesterolaemic agents. Clearly it must be involved in atherogenesis since its dysfunction leads to premature and severe atherosclerosis in both animals and man. The tools are now available to address this question and answers should be forthcoming in the near future.
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PMID:Pathophysiology of human lipoprotein receptors: clinical consequences of a cellular defect. 632 45

We performed a screening of exon 9 of the low density lipoprotein receptor (LDLR) gene in 14 Danish families with familial hypercholesterolemia (FH) using the denaturing gradient gel electrophoresis (DGGE) technique. In one of the probands from these families an abnormal band pattern in the gradient gel was detected. Subsequent DGGE analysis of the family of this index patient revealed that the DGGE pattern cosegregated with the disease in this family. Sequencing of the exon showed a deletion of a C in codon 424 of the LDLR gene resulting in a frame shift with the introduction of a stop codon 5 codons further downstream. The mutation is referred to as FH-Odense. The predicted truncated receptor protein consists of the 428 amino terminal amino acids. Consequently, the cytosolic and membrane spanning parts of the mature LDL receptor, which normally secure the receptor in the plasma membrane, are missing. The FH-Odense mutation results in severe premature coronary atherosclerosis as shown by the clinical expression in 5 generations of the affected family.
Atherosclerosis 1994 Dec
PMID:Detection of a single base deletion in codon 424 of the low density lipoprotein receptor gene in a Danish family with familial hypercholesterolemia. 771 23

Apolipoprotein (apo) E-deficient mice were fed a hypercholesterolemic diet for 14 weeks. Mean serum cholesterol levels rose to 37.5 mM. Upon complete necroscopy, massive xanthomatous lesions were noticed in various tissues, with a predilection for subcutaneous and peritendinous tissues, while control animals on the same diet (3.4 mM serum cholesterol) and apo E-deficient mice on a regular chow diet (20 mM serum cholesterol) did not show such lesions. Also, apo E3-Leiden transgenic mice fed a high fat diet, with 60 mM of serum cholesterol, did not exhibit any xanthomatosis. The xanthomatous lesions found in the Apoe knock-out mouse clearly differed in location from xanthomas previously found in low density lipoprotein receptor-deficient mice. We conclude that the lack of apo E results in atypical disseminated xanthomatosis, suggesting that apo E has an important role in determining the tissue distribution of cholesterol deposition.
Atherosclerosis 1995 Jan 20
PMID:Atypical xanthomatosis in apolipoprotein E-deficient mice after cholesterol feeding. 777 82

The population of Czechoslovakia is at high risk of premature atherosclerosis. Normal DNA polymorphism at the low density lipoprotein receptor (LDLR) locus detectable with the restriction enzyme PvuII was analyzed in Czech children with a high or a low concentration of total serum cholesterol. The PvuII restriction site was found significantly more often in the low cholesterol group than in the high cholesterol group. Thus, normal genetic variation at the LDLR locus contributes to the population variation in cholesterol in children in the population studied.
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PMID:Normal genetic variation at the low density lipoprotein receptor (LDLR) locus influences cholesterol levels in children. 809 97

The search for plasma lipoproteins began at the turn of the century. It was not until 1949 that a meeting of the Faraday Society celebrated the separation of the alpha and beta lipoproteins. At that moment, ultracentrifugists in Berkeley were already busily converting "alpha" to high density lipoprotein and "beta" to low density lipoprotein; the modern era of lipoproteins had begun. Over the succeeding 10 years, a quarrel over whether the level of Sf 0-20 or cholesterol was the more powerful risk factor ended with an eclipse of the analytical ultracentrifuge and a surge of interest in the biological side of lipoproteins. The postheparin clearing factor became lipoprotein lipase, and free fatty acids were discovered. In 1960, abetalipoproteinemia and Tangier disease suggested that the apolipoproteins must be specific and spurred a hunt for their number and nature. The first amino acid sequences aroused speculation of "amphipathic helices." By 1970, conversion of hyperlipidemia to five types of hyperlipoproteinemia led to worldwide fascination with electrophoretic patterns, "floating beta," and "the Friedewald formula" as codes for genetic abnormalities leading to early coronary artery disease. A few years later, the appearance of "familial combined hyperlipidemia" confounded the phenotyping, and the discovery of the low density lipoprotein receptor heralded the coming of true genotypes. This is a Bethesda-based story of the "climb to base camp" preceding the joining of molecular biology with the research on lipoproteins, dyslipoproteinemia, and atherosclerosis.
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PMID:Phenotyping. On reaching base camp (1950-1975). 846 75

As a species the mouse is highly resistant to atherosclerosis. However, through induced mutations it has been possible to develop lines of mice that are susceptible to this disease. For example, mice that are deficient in apolipoprotein E, a ligand important in lipoprotein clearance, develop atherosclerotic lesions resembling those observed in humans. These lesions are exacerbated when the mice are fed a high-cholesterol, high-fat, Western-type diet. Other promising models are mice that are deficient in the low density lipoprotein receptor and transgenic mice that express human apolipoprotein B and transdominant mutant forms of apolipoprotein E. These models are now being used to study the pathogenesis of atherosclerotic lesions, as well as the influence of genetics, environment, hormones, and drugs on lesion development.
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PMID:Mouse models of atherosclerosis. 861 28

A single base deletion (211delG) in the low density lipoprotein receptor (LDLR) gene was shown to cause familial hypercholesterolaemia (FH) in a large family from Northern Ireland. Twenty-four of 52 family members tested had this mutation, 13 of which were newly diagnosed. Mutation-positive individuals had significantly higher mean total-cholesterol (TC) and LDL-cholesterol (LDL-C) than those without 211delG. LDL-C was a more accurate indicator of disease status than TC. When TC levels alone were considered, in individuals over 16 years, a false negative rate (TC < 7.5 mmol/l) of 40% was found; however this fell to 13% based on inclusion of LDL-C levels. Individuals with coronary artery disease (CAD) had significantly higher TC levels than those without CAD and tended to have tendinous xanthomas (TX) and corneal arcus (CA). Generic polymorphisms in the angiotensin converting enzyme (ACE) and apolipoprotein (apo) B genes did not appear to be associated with lipid levels or with the clinical severity of the disease; however, the apo E epsilon4 allele did show a lipid-raising effect in individuals with the mutation.
Atherosclerosis 1996 Feb
PMID:A novel single base deletion in the LDLR gene (211delG): Effect on serum lipid profiles and the influence of other genetic polymorphisms in the ACE, APOE and APOB genes. 864 75

Lipoprotein lipase (LPL) is a key enzyme in the hydrolysis of triglyceride-rich lipoproteins. Conflicting results have been reported concerning its role in atherogenesis. To determine the effects of the overexpressed LPL on diet-induced atherosclerosis, we have generated low density lipoprotein receptor (LDLR) knockout mice that overexpressed human LPL transgene (LPL/LDLRKO) and compared their plasma lipoproteins and atherosclerosis with those in nonexpressing LDLR-knockout mice (LDLRKO). On a normal chow diet, LPL/LDLRKO mice showed marked suppression of mean plasma triglyceride levels (32 versus 236 mg/dl) and modest decrease in mean cholesterol levels (300 versus 386 mg/dl) as compared with LDLRKO mice. Larger lipoprotein particles of intermediate density lipoprotein (IDL)/LDL were selectively reduced in LPL/LDLRKO mice. On an atherogenic diet, both mice exhibited severe hypercholesterolemia. But, mean plasma cholesterol levels in LPL/ LDLRKO mice were still suppressed as compared with that in LDLRKO mice (1357 versus 2187 mg/dl). Marked reduction in a larger subfraction of IDL/LDL, which conceivably corresponds to remnant lipoproteins, was observed in the LPL/LDLRKO mice. LDLRKO mice developed severe fatty streak lesions in the aortic sinus after feeding with the atherogenic diet for 8 weeks. In contrast, mean lesion area in the LPL/LDLRKO mice was 18-fold smaller than that in LDLRKO mice. We suggest that the altered lipoprotein profile, in particular the reduced level of remnant lipoproteins, is mainly responsible for the protection by LPL against atherosclerosis.
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PMID:Suppression of diet-induced atherosclerosis in low density lipoprotein receptor knockout mice overexpressing lipoprotein lipase. 869 76


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