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

In 1973, studies with cultured human fibroblasts by Brown, Goldstein, and colleagues showed that receptor-mediated endocytosis of low-density lipoprotein (LDL) is the regulatory principle in cellular cholesterol homeostasis. The complete sequence of metabolic events associated with the binding, uptake, and degradation of these cholesterol-rich lipoprotein particles by mammalian cells has been termed the LDL receptor pathway. This important process has two main tasks. First, it supplies cells with cholesterol, thereby mediating the removal of cholesterol-rich lipoproteins from the circulation. Second, it protects cells from over-accumulation of cholesterol, because the cholesterol derived from lysosomal hydrolysis of LDL cholesterylesters exerts a series of feedback control mechanisms designed to maintain a constant level of cholesterol within the cell. Thus, high extracellular concentrations of LDL reduce cellular synthesis of cholesterol (by suppression of the activities of 3 hydroxy-, 3-methyl-glutaryl-CoA synthase and reductase, rate-limiting enzymes in cholesterol synthesis), stimulate its re-esterification, and decrease the number of LDL receptors, preventing further cellular entry of cholesterol. The suppression of LDL receptor activity by high plasma levels of LDL is beneficial for most cells, but the consequences caused by reduction of LDL receptor activity in the liver can be devastating. This is best documented in familial hypercholesterolemia (FH), in which defects in the LDL receptor gene disrupt the normal functions of the LDL receptor pathway. The clinical manifestation of the failure to remove LDL from the bloodstream at normal rates includes severe hypercholesterolemia and premature atherosclerosis. Some of the important findings that emerged from studies on structure/function relationships of the key player in the process, the LDL receptor itself, are described.
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PMID:Familial hypercholesterolemia: dissection of a receptor disease. 209 41

The main advances since 1980 in our understanding of atherosclerosis can be summarised under four headings. 1) The migration and proliferation of smooth muscle cells from the media into the intima are key-events of atherogenesis, and probably also of restenosis following percutaneous transluminal coronary angioplasty. The experimental study of their regulations, especially looking for inhibitors, has therefore gained increased interest as it may provide original approaches to the prevention of post-angioplasty restenosis. 2) The histiocytes/macrophages, derived from blood monocytes, also take a major part in the initiation of atherosclerotic lesions. An intensive research activity is now being devoted to elucidating the many facets of their participation in atherogenesis. 3) Brown and Goldstein's discoveries have explained the biochemical mechanisms of the increased plasma low-density lipoprotein (LDL) concentration found in familial hypercholesterolemia (type IIa), although they did not completely solve the enigma of lipid deposition in the arterial wall. The metabolic handling of modified LDLs appears to be crucial to the foamy transformation of macrophages and, possibly, of smooth muscle cells. 4) Risk factors identified by epidemiology are usually held responsible for atherosclerosis. Yet this causal interpretation is not entirely satisfactory, and alternative or complementary hypotheses are being but forward. Among them, the most consistent submits that a viral aggression of the arterial wall is involved in the genesis and progression of atherosclerosis.
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PMID:[New concepts of atherogenesis]. 283 18

Atherosclerosis appears to be a disease with a multifactorial pathogenesis. The factors participating in its etiology are called risk factors [Fejfar 1972; Stamler 1983]. These may be divided into a group of uninfluencible risk factors (age, sex, genetic load, etc.) and influencible risk factors of first or second order. Hyperlipidemia may be considered as influencible risk factor of the first order [Goldstein et al. 1973]. From this reason it is necessary to investigate the etiology of lipoprotein metabolic disorders and the possibilities of their treatment and prevention. Hormonal influences are also considered to be one of the influencible risk factors which may affect a number of steps in lipoprotein metabolism.
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PMID:The role of hormones in the regulation of lipoprotein metabolism (review). 391 Apr 9

Sixty-two subjects from 23 families were evaluated by serum lipid analyses and tissue culture biochemistry in skin fibroblasts. In 53 cases from 19 families with proven familial hypercholesterolemia (FHC), fibroblast cultures were successful. In 45 of these cases (85%) the clinical diagnosis of hyper- or normocholesterolemia was in accordance with the tissue culture findings. Four patients 2-38 years old, had hypercholesterolemia but normal tissue culture results. Four patients, 18-44 years old, had normal serum cholesterol levels for their age and sex, but were heterozygotes according to tissue culture results. In the remaining four families only the propositus had hypercholesterolemia. All members of the families including the propositus had normal tissue culture determinations indicating that not all cases of idiopathic hypercholesterolemia are due to the Goldstein-Brown mechanism of defective LDL receptor function.
Atherosclerosis 1981 Apr
PMID:Serum cholesterol levels in patients with familial hypercholesterolemia confirmed by tissue culture. 724 90

Many patients with hyperlipidemia are without symptoms, thus laboratory data are often the sole index of therapeutic success or failure. Aggressive laboratory investigation of patient and family may identify inherited hyperlipidemia long before the clinical manifestations of atherosclerosis. The classification system of Fredrickson et al and Goldstein et al are reviewed from an historical and a clinician's point of view. Specific phenotypes and phenocopies, their causes, clinical manifestations, and management are presented. The basic laboratory assessment of hyperlipidemia is described, specialized testing is reviewed, and promising new methodologies are discussed.
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PMID:The clinical laboratory and hyperlipidemia: a clinician's view. 728 62

An increasing body of evidence indicates that oxidized low density lipoprotein (LDL) is involved in the pathogenesis of atherosclerosis. One of the first biologic actions of oxidized LDL to be identified in vitro was its ability to interact with the 'acetyl LDL receptor' discovered by Goldstein and Brown. Over the past decade, considerable progress has been made in identifying and characterizing cell-surface receptors for oxidized LDL. Most of these receptors are thought to be multifunctional because they interact with several structurally different ligands, and accordingly have been termed 'scavenger receptors'. The objective of this article is to review the most important publications dealing with structure, ligand specificity, regulation, and function of scavenger receptors.
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PMID:Receptors for oxidized low density lipoprotein. 998 60

Cholesterol research was one of the key areas of scientific investigation in the 20th century. Little was known about the structure of cholesterol until the pioneering research of A. Windaus and H. Wieland in the first part of the century. The structure of cholesterol was completely elucidated in 1932. With the development of isotopic tracers in the 1930s studies on cholesterol biosynthesis were initiated. In 1942 K. Bloch and D. Rittenberg showed that deuterium-labeled acetate was incorporated into the ring structure and side chain of cholesterol. Another important discovery from Bloch's laboratory was that squalene was a precursor of cholesterol. In 1956, the main elements of the biosynthetic pathway became known when isopentenyl pyrophosphate was discovered as a precursor. In 1966, J. Cornforth and G. Popjak predicted that there were 16234 possible stereochemical pathways by which mevalonate could be converted into squalene. They subsequently showed which of these pathways was correct. In the 1970s and 1980s K. Bloch was able to provide intriguing evidence for an evolutionary advantage of cholesterol over lanosterol or some of the intermediates in the conversion of lanosterol to cholesterol. The last quarter of the 20th century was when M. Brown and J. Goldstein showed that the low density lipoprotein receptor was a key regulator of cholesterol homeostasis. They have also demonstrated that cholesterol balance in the cell is transcriptionally regulated via the sterol regulatory element binding protein. In the later part of the 20th century drugs were developed that effectively lower plasma cholesterol and lessen the risk of atherosclerosis and cardiovascular disease.
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PMID:Cholesterol in the year 2000. 1111 Oct 73

Considering the morphological findings in egyptian mummies at the beginning of the 20th century, atherosclerotic lesions were also apparent in pharaoh mummies more than 3500 years ago. Hippokrates (469-377 b.c.) described the sudden (cardiac) death, whereas Erasistratos had documented the typical claudication intermittens symptoms of peripheral arterial disease approximately 300 b.c. Later on in 1575, Fallopius observed severe pathological findings in arteries which he has characterized as a 'degeneration to bones', suggesting the presence of calcified atherosclerotic lesions. The relation between coronary lesions and the symptoms of angina pectoris was postulated in 1799 by Parry, however, only more than 80 years later angina pectoris was interpreted as a result of myocardial ischemia by Potain. During that time, the term 'arteriosclerosis' was firstly created by Lobstein in his 'Lehrbuch der pathologischen Anatomie', published in 1835. With the beginning of the last century, the pathophysiological aspects of plaque development were investigated in more detail by a number of researchers. In this context, people such as Saltykow, Chalatow and Anitschkow are important to notice. In 1914, Anitschkow firstly described the role of cholesterol accumulation in the vessel wall for the development of atherosclerosis. He used a cholesterol-fed rabbit model, which is the most important model of experimental atherosclerosis up to now. He also firstly described the 'Cholesterinesterphagozyten', which today commonly are known as foam cells, derived from macrophages. Using the cholesterol-fed rabbit model as well, already in 1942, Ludden et al. could demonstrate the atheroprotective effect of estrogen experimentally, a finding, which got later confirmed in the primate model and epidemiological studies. In the last three decades our knowledge has expanded by a large number of findings, based on morphological, immunohistological and molecular methods. In this context, one major contribution was the discovery of the LDL-receptor and its importance for the development of atherosclerosis by Brown and Goldstein, and the setting up of the 'response to injury hypothesis' by Ross and Glomset. At the present, we understand atherosclerosis as a complex (and at least in part as a physiological) phenomenon, beginning in the early childhood. The pathological aspect, making it to a disease, is depending on individual growth dynamics and plaque localization. The following key processes during the development of atherosclerosis are identified: 1) Endothelial injury, 2) intimal cholesterol accumulation and monocyte invasion with subsequent foam cell formation, 3) migration and proliferation of smooth muscle cells with expression of extracellular matrix 4) local thrombus formation with secondary organization 5) calcification and/or plaque rupture 6) final occlusion due to plaque rupture/thrombus formation. The classical concept of cardiovascular risk factors does only partially explain the origin of atherosclerosis. For the future, further mechanism(s) need to be identified and studied (genomic pathways, hormonal aspects, infective components, etc.) probably opening an effective therapeutical strategy to prevent and treat atherosclerotic diseases.
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PMID:The discovery of the pathophysiological aspects of atherosclerosis--a review. 1168 58

Our present knowledge on chemically modified proteins and their receptor systems is originated from a proposal by Goldstein and Brown in 1979 for the receptor for acetylated LDL which is involved in foam cell formation, one of critical steps in atherogenesis. Subsequent extensive studies using oxidized LDL (OxLDL) as a representative ligand disclosed at least 11 different scavenger receptors which are collectively categorized as "scavenger receptor family". Advanced glycation endproducts (AGE) and their receptor systems have been studied independently until recent findings that AGE-proteins are also recognized as active ligands by scavenger receptors including class A scavenger receptor (SR-A), class B scavenger receptors such as CD36 and SR-BI, type D scavenger receptor (LOX-1) and FEEL-1/FEEL-2. Three messages can be summarized from these experiments; (i) endocytic uptake of OxLDL and AGE-proteins by macrophages or macrophage-derived cells is mainly mediated by SR-A and CD36, which is an important step for foam cell formation in the early stage of atherosclerosis, (ii) selective uptake of cholesteryl esters of high density lipoprotein (HDL) mediated by SR-BI is inhibited by AGE-proteins, suggesting a potential pathological role of AGE in a HDL-mediated reverse cholesterol transport system, (iii) a novel scavenger receptor is involved in hepatic clearance of plasma OxLDL and AGE-proteins.
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PMID:Scavenger receptors for oxidized and glycated proteins. 1466 Oct 91

First, we will review the major episodes of the initial clinical investigations on lipoproteins. They were carried out in the 1950s, decade of the expansion of Biochemistry. Gofman and his colleagues, at Berkeley, established the power and versatility of the ultracentrifugation method to study the serum lipoproteins. This research group identified Low Density Lipoprotein cholesterol, rather than generic cholesterol as the atherogenic agent. In 1955, Havel et al. at Bethesda, reported a simpler method for the separation of serum lipoproteins by preparative ultracentrifugation, which permitted chemical analysis of defined fractions. However, there was an obvious need for a technique to undertake a screening of a population because the epidemiological Framingham Study, started in 1946, had confirmed serum cholesterol levels as a major risk factor of atherosclerosis. In 1967, Fredrickson et al. applying electrophoresis methods to the separation of lipoproteins developed a classification of lipoprotein disorders, which was somewhat controversial, but it is still a reference. Alaupovic, pursuing his apolipoprotein studies, introduced the ABC nomenclature, the one in use today. In 1973, Brown and Goldstein described the LDL receptor and its function on regulating cholesterol homeostasis, laying the foundations of a classification of hyperlipoproteinemias on a genetic basis. Then, we will review the genetic basis of lipoprotein disorders, through the work of several research groups, studying, mainly, mutations leading to hypercholesterolemias; most hypertrygliceridemias are not well defined in genetic terms.
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PMID:[From Fredrickson's classification of phenotypes--lipoprotein patterns--to genotype comprehension]. 1620 55


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