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)

Using differential hybridization techniques we have isolated a hamster cDNA encoding a cholesterol-regulated protein. By sequence homology we concluded that the isolated cDNA encodes alpha 1-inhibitor III (alpha 1 I3), a protein of the alpha-macroglobulin (alpha M) family. When hamsters were fed diets rich in cholesterol, cholic acid, or chenodeoxycholic acid, the amount of alpha 1I3 RNA was reduced between 5- and 10-fold. Drugs that lower plasma cholesterol levels, such as colestipol and mevinolin, increased alpha 1I3 RNA between 2- and 3-fold. Additionally, plasma alpha 1I3 protein levels, as measured by immunoblotting techniques using an anti-human alpha 2M antibody, correlate well with alpha 1I3 RNA levels in those hamsters. Plasma alpha 1I3 protein was inversely proportional to plasma cholesterol levels in those hamsters. The observed suppression of alpha 1I3 expression by cholesterol mimics the cholesterol-mediated regulation of other genes that maintain cholesterol homeostasis, such as 3-hydroxy-3-methylglutaryl coenzyme A synthase, 3-hydroxy-3-methylglutaryl coenzyme A reductase, and low density lipoprotein receptor. We hypothesize that alpha 1I3 may play a role in the onset of atherosclerosis and may provide a link between cholesterol and the clotting system. Furthermore, the availability of another sterol-regulated gene, like alpha 1I3, should help elucidate the molecular mechanisms of cholesterol-mediated regulation of gene transcription.
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PMID:Cholesterol-mediated suppression of alpha 1-inhibitor III, a plasma alpha-macroglobulin family protein. 171 65

Regulation of expression of the genes for the low density lipoprotein receptor (LDLR) and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR) is of central importance in the control of cholesterol metabolism and thus in influencing the concentration of low density lipoprotein in the plasma. This can be studied by investigating the effects of factors (hormones, drugs, etc.) on the levels of mRNA for these genes. An RNase protection assay is reported for measurement of the levels of mRNA for the LDLR and HMGR. Several probes have been developed for these genes, together with probes for the "housekeeping" genes, beta-actin and glyceraldehyde-3-phosphate dehydrogenase. Various conditions in the assay have been examined and optimised, e.g. conditions for solution hybridization and RNase digestion and the use of "sense" RNA standards. The assay allows accurate measurement of approximately 2 x 10(7) copies of LDLR and HMGR mRNAs, which is equivalent to the number of copies present in approximately 1 x 10(6) human dermal fibroblasts and approximately 5 x 10(5) Hep G2 liver hepatoma cells cultured in 10% fetal calf serum. The average number of copies of mRNA per cell was estimated in fibroblasts and Hep G2 cells under various conditions of regulation of the LDLR and revealed the following: [table: see text] Under the chosen conditions 10 copies per cell was the detection limit for the assay. The effect of these treatments on the number of copies of mRNA per cell for beta-actin and glyceraldehyde-3-phosphate dehydrogenase was also determined.
Atherosclerosis 1991 Sep
PMID:A sensitive RNase protection assay for the quantitation of the mRNAs for the LDL receptor and HMG-CoA reductase in human total RNA. Effects of treatments on cells in culture designed to up- and down-regulate expression of the LDL receptor. 182 10

It has recently been suggested that a substitution of glutamine for arginine at residue 3500 of apolipoprotein (apo) B-100 causes familial defective apo B-100 (FDB), an autosomal, dominantly inherited disorder, which leads to increased serum cholesterol levels. From a sample of 243 patients from Munich with type IIa hyperlipoproteinemia (HL), we have identified eight individuals with the apo B-100 arginine(3500)----glutamine mutation. In a group of 57 subjects with defective low density lipoprotein receptor (LDLR), no mutant apo B alleles were detected. The frequency of FDB in patients with type IIa HL was estimated to be 3%. In the kindreds of three of the probands, 10 additional carriers of the apo B mutation were identified. Clinical and biochemical data reveal a striking similarity between patients with FDB and those with a defect in the LDLR gene. Our data support previous findings that FDB is a serious disorder causing premature atherosclerosis.
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PMID:Familial defective apolipoprotein B-100. Comparison with familial hypercholesterolemia in 18 cases detected in Munich. 216 82

Familial hypercholesterolemia is an inherited disease in humans that is caused by a deficiency in the receptor that mediates the internalization and degradation of low density lipoprotein. Patients that inherit two abnormal low density lipoprotein receptor alleles have severe hypercholesterolemia, advanced atherosclerosis, and life-threatening coronary artery disease that is refractory to conventional therapies. In this review, we discuss the prospects for gene therapy in the treatment of familial hypercholesterolemia.
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PMID:Prospects for gene therapy of familial hypercholesterolemia. 221 9

The low density lipoprotein receptor removes the cholesterol-carrying lipoproteins from blood. When the activity of LDL receptors is reduced, as a result of genetic or acquired abnormalities, LDL increases in blood, resulting in atherosclerosis. Heterozygote familial hypercholesterolemia (one mutant gene) is characterized by a 50% reduction of LDL receptors leading to twofold increases of LDL. In homozygote familial hypercholesterolemia (two mutant genes), there are no active LDL receptors. So very high cholesterol blood levels are observed and severe atherosclerosis ensues. FH heterozygotes can be treated with drugs that stimulate the cells to produce more LDL receptors. Because these are under negative feed-back regulation by intracellular cholesterol, depletion of intracellular cholesterol in the liver through administration of bile acid-binding resins and cholesterol synthesis inhibitors activates the synthesis of LDL receptors. The ingestion of a die rich in cholesterol and saturated fatty acids reduce the LDL receptors in the liver. This may contribute in part to the widespread occurrence of high cholesterol levels and atherosclerosis in western societies.
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PMID:[LDL receptors]. 229 88

A modified strain of heritable hyperlipidaemic rabbit has been produced by crossing male albino rabbits homozygous for low density lipoprotein receptor deficiency into a coloured commercial colony with strong breeding characteristics. The genetic deficiency has been preserved in the resulting offspring through many generations. Litter numbers, live weight gains and energy intake are similar to normal rabbits. Free and esterified cholesterol in serum, and total cholesterol in very low density plus low density lipoproteins, are markedly increased in homozygote, but only slightly raised in heterozygote, animals. High density lipoprotein-cholesterols show an opposite trend but with less marked differences between the genetic strains. Liver total and esterified cholesterol levels were substantially increased in homozygotes, and the ability of liver membranes to bind human 125I-LDL was markedly reduced, owing to a reduction of the number of high-affinity binding sites. All animals with serum cholesterol values greater than 14 mmol/l at weaning developed extensive aortic atherosclerosis within 16 weeks. The early lesions had the histological appearances of fatty streaks and progressed to complicated disease at 6-12 months. A distinctive pattern of calcific arteriosclerosis, quite different from atherosclerosis, was observed in most aging heterozygote animals and was associated with extensive renal calcium deposition. Corneal arcus developed in some homozygotes but there was no evidence of cerebral atherosclerosis. We conclude that homozygotes of this modified strain can be used for macroscopic studies of the progression of aortic atherosclerosis in the first 4 months after weaning but after this period a combination of macroscopic and microscopic techniques are required. Heterozygotes are unsuitable for studies of this nature.
Atherosclerosis 1988 Jun
PMID:Biochemical and pathological features of a modified strain of Watanabe heritable hyperlipidaemic rabbits. 340 Dec 89

The clinical and laboratory features of genetic hyperlipoproteinaemia (HLP) in 10 black patients attending the Lipid Clinics at Groote Schuur Hospital and Red Cross War Memorial Children's Hospital are reported. Five had type III HLP characterized by severe cutaneous xanthomas, which facilitated initial detection. Three adult patients suffered from heterozygous primary hypercholesterolaemia compatible with the diagnosis of familial hypercholesterolaemia (FH) caused by a low density lipoprotein receptor defect. They differed, however, from the typical presentation in lacking the Achilles tendon xanthomas characteristic of this condition. One patient presented in childhood with an unusual form of homozygous FH; the remaining patient had type V HLP. Seven of the 10 patients were male and most had risk factors for atherosclerosis in addition to the HLP. Despite the fact that the average age of the 9 adult patients is at present 52 years, only 1 has manifested overt atherosclerotic vascular disease. Compliance with therapy was variable but a generally satisfactory response was obtained in about half the patients, the reduction of plasma lipids in the type IIa subjects being disappointing. These data point to an important area for future study.
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PMID:A diversity of genetic hyperlipoproteinaemias in black patients. Experience at the Lipid Clinics at Groote Schuur Hospital and Red Cross War Memorial Children's Hospital, Cape Town. 377 67

A strain of pigs bearing three immunogenetically defined lipoprotein-associated markers (allotypes), designated Lpb5, Lpr1, and Lpu1, has marked hypercholesterolemia on a low fat, cholesterol-free diet. Unlike individuals with familial hypercholesterolemia or WHHL rabbits, the affected pigs have normal low density lipoprotein receptor activity. The animals, by 7 months of age, have extensive atherosclerotic lesions in all three coronary arteries. This strain of pig represents an animal model for atherosclerosis and hypercholesterolemia associated with mutations affecting the structures of plasma lipoproteins. One of the variant apolipoproteins, Lpb5, is apolipoprotein-B. A second variant apolipoprotein (Lpr1), termed apo-R, is a 23-kilodalton protein present in both the very low density (d less than 1.006 g/ml) and the very high density (d greater than 1.21 g/ml) fractions of pig plasma. Isoforms of this protein correlate with two Lpr alleles, Lpr1 and Lpr2. The Lpr genes segregate independently of the Lpb5 and Lpu1 alleles. The Lpu1 allotype is a component of low density lipoprotein and is genetically linked to Lpb5.
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PMID:Lipoprotein mutations in pigs are associated with elevated plasma cholesterol and atherosclerosis. 378 63

Diabetes mellitus is associated with severe and premature cardiovascular disease. The reasons for this have not been identified. It is now apparent that diabetics often have elevated circulating insulin levels compared to non-diabetics. In non-insulin dependent diabetes this is due to the associated obesity while in insulin treated diabetics exogenous insulin is responsible for hyperinsulinaemia between meals and at night. Two reports of high insulin levels in non-insulin dependent diabetics with cardiovascular disease are consistent with clinical and epidemiological studies linking hyperinsulinaemia with coronary, cerebral and peripheral arterial disease in non-diabetics. The arterial wall is an insulin sensitive tissue. Insulin promotes proliferation of arterial smooth muscle cells and enhances lipid synthesis and low density lipoprotein receptor activity. Insulin also promotes experimental atherosclerosis in a number of species. The evidence linking hyperinsulinaemia to the cardiovascular complications and diabetes is suggestive but incomplete and much more information on predictive factors for arterial disease in diabetes is urgently required. Diabetes mellitus is associated with severe and premature cardiovascular disease (reviewed by Stout 1982). Ischaemic heart disease, stroke and peripheral vascular disease are all more common in diabetics, particularly diabetic women. Although there is evidence for the existance of a specific diabetic cardiomyopathy, much of the cardiovascular disease in diabetics is due to atherosclerosis and its complications. Arterial disease in diabetics in distinct from microvascular disease affecting capillaries, and does not differ morphologically or biochemically from atherosclerosis in non-diabetics. The reason for the increased incidence of atherosclerosis in diabetes has not been established. Both non-insulin dependent and insulin dependent diabetes appear to be associated with cardiovascular disease.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Hyperinsulinaemia--a possible risk factor for cardiovascular disease in diabetes mellitus. 390 79

We examine the hypothesis of Portman et al. (1970) that lysolecithin is a causal agent of atherosclerosis. Four lines of argument support this hypothesis. (1) Lysolecithin is present, taken up and can act. Large amounts of lysolecithin are formed in plasma concomitant with triglyceride transport and it is readily taken up by arteries and retained for some time. Lysolecithin in aortic intima increases several-fold early in the induction of atherosclerosis in animals. From model system studies it is plausible that physiological doses of lysolecithin have physiologically significant effects. (2) At least one plausible mechanism of action can be formulated: stimulation of smooth muscle cell division due to lysolecithin-increased Ca2+ uptake. (3) The hypothesis is consistent with, and rationalizes, many literature observations in that inferred lysolecithin levels or production rates are appropriately correlated with a variety of positive and negative risk factors to a degree highly unlikely by chance. We found no data contradicting the hypothesis and only one piece weakening it. (4) A mechanism is outlined showing that low density lipoprotein receptor deficiency, the severest known risk factor, should cause the delivery of very high lysolecithin doses to artery walls. We conclude that the evidence, although indirect, is strong enough to give direct tests a high priority.
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PMID:Evidence that lysolecithin is an important causal agent of atherosclerosis. 403 62


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