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)

Tangier disease is an autosomal recessive genetic disorder characterized by a severe high-density lipoprotein (HDL) deficiency, sterol deposition in tissue macrophages, and prevalent atherosclerosis. Mutations in the ATP binding cassette transporter ABCA1 cause Tangier disease and other familial HDL deficiencies. ABCA1 controls a cellular pathway that secretes cholesterol and phospholipids to lipid-poor apolipoproteins. This implies that an inability of newly synthesized apolipoproteins to acquire cellular lipids by the ABCA1 pathway leads to their rapid degradation and an over-accumulation of cholesterol in macrophages. Thus, ABCA1 plays a critical role in modulating flux of tissue cholesterol and phospholipids into the reverse cholesterol transport pathway, making it an important therapeutic target for clearing excess cholesterol from macrophages and preventing atherosclerosis.
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PMID:Tangier disease and ABCA1. 1111 Oct 99

Atherosclerotic cardiovascular disease (CVD) remains the leading cause of morbidity and mortality in Western societies. Although cholesterol is a major CVD risk factor, therapeutic interventions to lower plasma cholesterol levels have had limited success in reducing coronary events. Thus, novel approaches are needed to reduce or eliminate CVD. A potential therapeutic target is a newly discovered ATP binding cassette transporter called ABCA1, a cell membrane protein that is the gateway for secretion of excess cholesterol from macrophages into the high density lipoprotein (HDL) metabolic pathway. Mutations in ABCA1 cause Tangier disease, a severe HDL deficiency syndrome characterised by accumulation of cholesterol in tissue macrophages and prevalent atherosclerosis. Studies of Tangier disease heterozygotes revealed that the relative activity of ABCA1 determines plasma HDL levels and susceptibility to CVD. Drugs that induce ABCA1 in mice increase clearance of cholesterol from tissues and inhibit intestinal absorption of dietary cholesterol. Thus, ABCA1-stimulating drugs have the potential to both mobilise cholesterol from atherosclerotic lesions and eliminate cholesterol from the body. By reducing plaque formation and rupture independently of the atherogenic factors involved, these drugs would be powerful agents for treating CVD.
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PMID:Novel approaches to treating cardiovascular disease: lessons from Tangier disease. 1122 43

Atherosclerosis constitutes the most common medical and surgical problem. This can be manifested clinically as stroke, coronary artery disease, or peripheral vascular disease. In the present review the microscopic appearance of the normal arterial wall, the definition of atherosclerosis and the five theories of atherogenesis are described. These are: the lipid theory, the hemodynamic theory, the fibrin incrustation theory, the nonspecific mesenchymal hypothesis and the response to injury hypothesis. Based on the above theories the sequence of events in atherogenesis is analyzed. The classification of the atherosclerotic lesions according to Stary (types I-VI) and their characteristics appear in a table. The epidemiology and the role of the following risk factors are presented in detail: age, sex, lipid abnormalities, cigarette smoking, hypertension, diabetes mellitus, physical inactivity, alcohol consumption, obesity, and hemostatic factors. In addition, less common genetically determined associations like homocystinuria, Tangier disease, Hutchinson-Gilford syndrome (progeria), Werner's syndrome, radiation induced atherosclerosis and the implications of Chlamydia pneumoniae on the arterial wall are discussed.
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PMID:The genesis of atherosclerosis and risk factors: a review. 1122 92

The present study examines the expression of ATP-binding cassette transporter 1 (ABC1) mRNA in normal and atherosclerotic tissues by using in situ hybridization in an effort to better understand the function of this cholesterol transport protein. Samples of normal baboon tissues as well as human normal and atherosclerotic aortas were hybridized with (35)S-labeled ABC1 sense and antisense riboprobes. Widespread expression of ABC1 was observed generally in tissues containing inflammatory cells and lymphocytes. Other noninflammatory cells that were also sites of ABC1 synthesis included the ductal cells of the kidney medulla, Leydig cells in the testis, and glial cells in the baboon cerebellum. Although normal veins and arteries did not express ABC1 mRNA, it was found to be upregulated in the setting of atherosclerosis, where widespread expression was found in macrophages within atherosclerotic lesions. These results are consistent with the proposed role of ABC1 in cholesterol transport in inflammatory cells. The specific upregulation of ABC1 mRNA in the setting of atherosclerosis probably reflects the response of leukocytes to cholesterol loading. However, the presence of ABC1 in ductal cells of the kidney medulla and in the small intestine suggest a more general role for this protein in cholesterol transport in other cell types.
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PMID:Localization of human ATP-binding cassette transporter 1 (ABC1) in normal and atherosclerotic tissues. 1123 17

The proportions of plasma high and low density lipoprotein cholesterol have been linked to inherited tendency for atherosclerosis in humans. Studies were conducted with Japanese quail males from lines genetically selected for high and low TC and a randombred (unselected) control line that were fed 0.0 or 0.5% cholesterol for 12 weeks. Atherosclerotic plaques were more severe in the high than in the low line quail and in those fed cholesterol compared to non-cholesterol-fed quail. Serum TG, TC, VLDLC, LDLC, and HDLC were also higher in the high than in the low line quail and in cholesterol-fed vs. non-cholesterol-fed quail. Significant interactions indicated that TC and LDLC concentrations were more affected by dietary cholesterol in the high line than in the low line. The low line quail maintained higher HDLC and lower LDLC than the high line. Regression and correlation analyses revealed that although VLDLC, LDLC, and TC were significant predictors of atherosclerosis in the high line birds, the TC/HDLC ratio was a better predictor in the low line. The Japanese quail lines used herein represent useful experimental models for studies of genetic differences in atherosclerosis in humans.
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PMID:Total cholesterol, total triglycerides, and cholesterol distribution among lipoproteins as predictors of atherosclerosis in selected lines of Japanese quail. 1124 92

The proband is a 50 year-old woman born from a consanguineous marriage. She has been suffering from angina pectoris since the age of 38 and underwent coronary bypass surgery for three-vessel disease at 48. The presence of low plasma levels of total cholesterol and high density lipoprotein (HDL) cholesterol (2.4 and 0.1 mmol/l) and apo AI (<15 mg/dl), associated with corneal lesions and a mild splenomegaly suggested the diagnosis of Tangier disease. However, none of the other features of Tangier disease, including hepatomegaly, anemia and peripheral neuropathy, were present. The analysis of the dinucleotide microsatellites located in chromosome 9q31 region demonstrated that the proband was homozygous for the alleles of D9S53, D9S1784 and D9S1832. The mother and son of the proband, both with low levels of HDL cholesterol, shared one of the proband's haplotypes, whereas neither of these haplotypes was present in the normolipidemic proband's sister. The sequence of ATP-binding cassette transporter 1 (ABC1-1) cDNA obtained by reverse transcription-PCR (RT-PCR) of total RNA isolated from cultured fibroblasts showed that the proband was homozygous for a C>T transition in exon 13, which caused a tryptophane for arginine substitution (R527W). This mutation was confirmed by direct sequencing of exon 13 amplified from genomic DNA. It can be easily screened, as the nucleotide change introduces a restriction site for the enzyme Afl III. R527W substitution occurs in a highly conserved region of the NH2 cytoplasmic domain of ABC1 protein. R527W co-segregates with the low HDL phenotype in the family and was not found in 200 chromosomes from normolipidemic individuals.
Atherosclerosis 2001 Feb 15
PMID:A point mutation in ABC1 gene in a patient with severe premature coronary heart disease and mild clinical phenotype of Tangier disease. 1125 60

HDL cholesterol (HDL-C) deficiency is the most common lipid abnormality observed in patients with premature coronary heart disease (CHD). Recently, our laboratory and others demonstrated that mutations in the ATP-binding cassette transporter 1 (ABCA1) gene are responsible for Tangier disease, a rare genetic disorder characterized by severely diminished plasma HDL-C concentrations and a predisposition for CHD. To address the question of whether common variants within the coding sequence of ABCA1 may affect plasma HDL-C levels and CHD risk in the general population, we determined the frequencies of three common ABCA1 variants (G596A, A2589G and G3456C) in men participating in the Veterans Affairs Cooperative HDL Cholesterol Intervention Trial (VA-HIT), a study designed to examine the benefits of HDL raising in men having low HDL-C (< or =40 mg/dl) and established CHD, as well as in CHD-free men from the Framingham Offspring Study (FOS). Allele frequencies (%) in VA-HIT were 31, 16, and 4 for the G596A, A2589G, and G3456C variants, respectively, versus 27, 12, and 2 in FOS (P<0.03). None of the variants were significantly associated with plasma HDL-C concentrations in either population; however, in VA-HIT, the G3456C variant was associated with a significantly increased risk for CHD end points, suggesting a role for this variant in the premature CHD observed in this population.
Atherosclerosis 2001 Feb 15
PMID:Common variants in the gene encoding ATP-binding cassette transporter 1 in men with low HDL cholesterol levels and coronary heart disease. 1125 61

Identification of mutations in the ATP binding cassette transporter (ABCA1) gene in patients with Tangier disease, who exhibit reduced HDL cholesterol (HDL-C) and apolipoprotein A1 (apoA1) levels and premature coronary atherosclerosis, has led to the hypothesis that common polymorphisms in the ABCA1 gene could determine HDL-C and apoA1 levels and the risk of coronary atherosclerosis in the general population. We sequenced a 660-bp 5' fragment of the ABCA1 gene in 24 subjects and identified 3 novel polymorphisms: -477C/T, -419A/C, and -320G/C. We developed assays, genotyped 372 participants in the prospective Lipoprotein Coronary Atherosclerosis Study (LCAS), and determined the association of the variants with fasting plasma lipids and indices of quantitative coronary angiograms obtained at baseline and 2.5 years after randomization to fluvastatin or placebo. Distribution of -477C/T and -320G/C genotypes were 127 CC, 171 CT, and 74 TT and 130 GG, 168 GC, and 75 CC, respectively, and were in complete linkage disequilibrium (P<0.0001). Data for -477C/T are presented. The -419A/C variant was uncommon (present in 1 of 63 subjects). Heterozygous subjects had a modest reduction in HDL-C (P=0.09) and apoA1 (P=0.05) levels and a lesser response of apoA1 to treatment with fluvastatin (P=0.04). The mean number of coronary lesions causing 30% to 75% diameter stenosis was greater in subjects with the TT genotype (3.1+/-2.1) or CT genotype (2.9+/-1.9) than in subjects with the CC genotype (2.2+/-1.8) (P=0.002). Similarly, compared with subjects with the CC genotype, greater numbers of subjects with the TT or CT genotype had >/=1 coronary lesion (P=0.001). No association between the genotypes and progression of coronary atherosclerosis or clinical events was detected. We conclude that ABCA1 genotypes are potential risk factors for coronary atherosclerosis in the general population.
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PMID:Novel polymorphisms in promoter region of atp binding cassette transporter gene and plasma lipids, severity, progression, and regression of coronary atherosclerosis and response to therapy. 1134 92

Tangier disease (TD) is characterized by severe high-density lipoproteins (HDL) deficiency, hypercatabolism of HDL constituents, impaired cellular cholesterol efflux, and mutations in the gene of ATP-binding cassette 1 (ABC-1). In the present study, we determined plasma lipid and apolipoprotein levels, and HDL subpopulations, in 110 subjects from a large TD kindred in which the proband was homozygous for an A-->C missense mutation at nucleotide 5338 of the ABC-1 transcript. In the proband HDL-C, apoA-I, and apoA-II concentrations were 2, 1, and 2 mg/dl, respectively, apoA-I was present only in prebeta(1), while apoA-II was found free of apoA-I in two distinct alpha mobility subpopulations with different sizes. The smaller size particles contained only apoA-II while the larger one contained apoA-II and apo(a). Relative to unaffected male relatives (n=30), male heterozygotes (n=21) had significant reductions (P<0.001) in plasma HDL-C (-45%), apoA-I (-34%), apoA-II (-59%), apoA-IV (-40%), Lp(a) (-62%), and apoB (-55%) concentrations, and a significant increase (P<0.05, +33%) in plasma apoC-III levels. Female heterozygotes (n=11) similarly had significant reductions (P<0.001) in the concentrations of plasma HDL-C (-42%), apoA-I (-27%), apoA-II (-52%), Lp(a) (-27%), and (P<0.01) apoA-IV (-28%), apoB (-13%), and a significant increase (P<0.05) in plasma apoE levels (+29%) as compared to unaffected female relatives (n=41). Large size HDL subpopulations, especially the two LpA-I particles: alpha(1) and prealpha(1) were dramatically reduced in both male and female heterozygotes relative to their unaffected family members. Since apoA-II decreased more than apoA-I in both male and female heterozygotes, the ratios of apoA-I/apoA-II were significantly (P<0.01) increased. The prevalence of CHD was 60% higher in the 32 heterozygotes than in the 71 unaffected relatives even though the latter group was on average 7 years older. We conclude that TD homozygotes have only prebeta(1) apoA-I-containing HDL subpopulations, while heterozygotes have HDL that is selectively depleted in the large alpha(1), prealpha(1), and alpha(2), prealpha(2) subpopulations, resulting in HDL particles that are small in size, poor in cholesterol, but relatively enriched in apoA-I compared to those of their unaffected relatives. These abnormalities appear to result in a higher risk of CHD in heterozygotes than in unaffected controls.
Atherosclerosis 2001 May
PMID:Subpopulations of high density lipoproteins in homozygous and heterozygous Tangier disease. 1136 17

Apolipoprotein E (apoE) produced by macrophages in the arterial wall protects against atherosclerosis, but the regulation of its secretion by these cells is poorly understood. Here we investigated the contribution of the adenosine triphosphate binding cassette transporters ABCA1 and ABC8 to the secretion of apoE from either primary human monocyte-derived macrophages (HMDM) or human THP1 macrophages. During incubations of up to 6 h, apoE secretion from both THP1 macrophages and HMDM was stimulated by 8-Br-cAMP, which activates ABCA1 expression. The putative ABCA1 inhibitor glyburide and antisense oligonucleotides directed against ABCA1 mRNA significantly reduced apoE secretion from THP1 macrophages and HMDM. Antisense oligonucleotides directed against ABC8 mRNA also inhibited apoE secretion, although this inhibition was less pronounced and consistent than in the case of ABCA1. ApoE secretion from HMDM of ABCA1-deficient patients with Tangier disease was also decreased. ApoE mRNA expression was not affected by inhibition of ABCA1 or ABC8 in normal HMDM or the lack of functional ABCA1 in HMDM from Tangier disease patients. Inhibition of ABCA1 in HMDM prevented the occurrence of anti-apoE-immunoreactive granular structures in the plasma membrane. We conclude that ABCA1 and, to a lesser extent, ABC8 both promote secretion of apoE from human macrophages.
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PMID:ATP binding cassette transporter ABCA1 modulates the secretion of apolipoprotein E from human monocyte-derived macrophages. 1142 87


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