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)

Activated lipid-laden macrophages in the vascular wall are key modulators of the inflammatory processes underlying atherosclerosis. We demonstrate here that the ATP-binding cassette (ABC) transporter ABCA1 is induced during differentiation of human monocytes into macrophages. ABCA1 has been implicated in macrophage interleukin-1beta secretion and apoptosis. Moreover, ABCA1 mRNA and protein levels are strongly upregulated by uptake of modified LDL and downregulated by HDL(3)-mediated lipid efflux in macrophages. Mutation analysis in patients with the classical Tangier disease (TD), a monogenetic disorder characterized by hypersplenism, macrophage accumulation and deposition of cholesteryl esters in the reticuloendothelial system, low plasma HDL and premature atherosclerosis, revealed deleterious mutations in their ABCA1 gene. The localization pattern of the mutations within the ABCA1 protein appears to determine the tropism for either the reticuloendothelial system, as seen in the classical TD phenotype, or the artery wall, as in the case of HDL deficiency in the absence of splenomegaly. In a comprehensive analysis of the expression and regulation of all currently known human ABC transporters, we identified additional cholesterol-responsive genes that are induced during monocyte differentiation into macrophages. Our results indicate a dual regulatory function for ABCA1 in macrophage lipid metabolism and inflammation.
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PMID:ATP-binding cassette transporter A1 (ABCA1) in macrophages: a dual function in inflammation and lipid metabolism? 1072 92

The ABCA1 gene, a member of the ATP-binding cassette A (ABCA1) transporter superfamily, encodes a membrane protein that facilitates the cellular efflux of cholesterol and phospholipids. Mutations in ABCA1 lead to familial high density lipoprotein deficiency and Tangier disease. We report the complete human ABCA1 gene sequence, including 1,453 bp of the promoter, 146,581 bp of introns and exons, and 1 kb of the 3' flanking region. The ABCA1 gene spans 149 kb and comprises 50 exons. Sixty-two repetitive Alu sequences were identified in introns 1-49. The transcription start site is 315 bp upstream of a newly identified initiation methionine codon and encodes an ORF of 6,783 bp. Thus, the ABCA1 protein is comprised of 2,261 aa. Analysis of the 1,453 bp 5' upstream of the transcriptional start site reveals multiple binding sites for transcription factors with roles in lipid metabolism. Comparative analysis of the mouse and human ABCA1 promoter sequences identified specific regulatory elements, which are evolutionarily conserved. The human ABCA1 promoter fragment -200 to -80 bp that contains binding motifs for SP1, SP3, E-box, and AP1 modulates cellular cholesterol and cAMP regulation of ABCA1 gene expression. These combined findings provide insights into ABCA1-mediated regulation of cellular cholesterol metabolism and will facilitate the identification of new pharmacologic agents for the treatment of atherosclerosis in humans.
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PMID:Complete genomic sequence of the human ABCA1 gene: analysis of the human and mouse ATP-binding cassette A promoter. 1088 28

Liver X receptors (LXRs) are members of the nuclear receptor superfamily that are involved in regulation of cholesterol transport and metabolism. Expression of cholesterol 7alpha-hydroxylase, cholesteryl ester transfer protein and certain ATP-binding cassette transporters that are responsible for cholesterol efflux from cells is regulated by LXR and its ligands. In this report we show that 5alpha, 6alpha-epoxycholesterol-3-sulfate (ECHS) and 7-ketocholesterol-3-sulfate inhibit transactivation of a reporter gene by LXR. Non-sulfated forms of these compounds, as well as many other steroid sulfates, had no antagonistic activity. Using chimeric receptors, the antagonistic activity of ECHS was dependent on its interaction with the ligand-binding domain of LXR. ECHS disrupts recruitment of the co-activator Grip 1 into a complex with agonist-bound LXR and this may be responsible for the observed antagonistic properties of these compounds. In various cultured cells, these LXR antagonists also promote de novo cholesterol synthesis and apoptosis. 7-Ketocholesterol and 5alpha, 6alpha-epoxycholesterol are present in blood and have been found in atherosclerotic plaques. If sulfated forms of these oxidized sterols are also present, they may have an important role in foam cell formation by inhibiting LXR function. Since LXR agonists can counteract the activity of these antagonists, they may have therapeutic potential against atherosclerosis.
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PMID:Auto-oxidized cholesterol sulfates are antagonistic ligands of liver X receptors: implications for the development and treatment of atherosclerosis. 1118 36

ATP-binding cassette (ABC) proteins form a group of highly conserved cellular transmembrane transporters. Studies over the past year have implicated ABC transporters in cellular lipid trafficking processes. This notion has recently been confirmed and extended by the finding that the ABC transporter ABCA1 is a key regulator of high-density lipoprotein (HDL) metabolism and macrophage targeting to the RES or the vascular wall. Expression of a large number of ABC transporters in monocytes/macrophages and their regulation by cholesterol flux render these transporter molecules potentially critical players in chronic inflammatory diseases such as atherosclerosis.
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PMID:ABC transporters and cholesterol metabolism. 1122 79

Atherosclerosis and its major clinical manifestation, coronary heart disease, is and will remain the main cause of mortality. Reviews on this subject dealt with factors that enhance development of atherosclerosis. This review deals with a new facet, that some individuals are less prone to develop atherosclerosis: (1) despite high cholesterol intake or (2) despite hypercholesterolemia with elevated low-density lipoprotein cholesterol (LDL-C) levels. The variability of response of plasma cholesterol to dietary intake was shown to be regulated by liver x receptor (LXR) that determines the rate of intestinal cholesterol absorption through the ATP-binding cassette (ABC) gene family. Other gene products, such as apolipoprotein-E (apo-E), scavenger receptor-B1 (SR-B1) and acyl coenzyme: cholesterol acyltransferase-2 (ACAT-2) affect cholesterol absorption also. The role of a genetic background for relative resistance to atherosclerosis is highlighted by subjects with familial hypercholesterolemia in whom high plasma cholesterol levels has not curtailed their expected life span. Studies in animals have shown that resistance to atherosclerosis in spite of hypercholesterolemia is affected by factors such as high-density lipoprotein (HDL) phospholipids that enhance reverse cholesterol transport, non-responsiveness to induction or lack of monocyte chemotactic protein-1 (MCP-1), C-C chemokine receptor 2 (CCR2), macrophage colony stimulating factor (MCSF), or vascular cell adhesion molecule-1 (VCAM-1). Since macrophages have been regarded as pro- or anti-atherogenic, evidence was collated that the high activity of scavenger receptors may contribute towards resistance to atherosclerosis if accompanied by adequate amounts of apo-E for cholesterol removal.
Atherosclerosis 2002 Jan
PMID:Is there a genetic basis for resistance to atherosclerosis? 1175 17

Macrophages play a central role in the initiation and progression of atherosclerotic lesions. In the nascent lesion, macrophages transform into foam cells through the excessive accumulation of cholesteryl esters. Dysfunctional lipid homeostasis in macrophages and foam cells ultimately results in the breakdown of membrane integrity and cell death. Studies within the past 2 years have implicated a defined subset of multispan transmembrane proteins, the ATP-binding cassette (ABC) transporters, in macrophage lipid homeostasis. The recent finding that ABCA1, beyond its function as a major regulator of plasma high-density lipoprotein metabolism, exerts significant antiatherosclerotic activities has provided the first direct evidence for the role of an ABC transporter in the pathogenesis of atherosclerosis.
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PMID:ATP-binding cassette (ABC) transporters in atherosclerosis. 1193 23

Numerous ATP-binding cassette (ABC) transporters are expressed in monocyte-derived macrophages and are subject to sterol-dependent regulation. ABCA1 has been identified as a key regulator of macrophage cholesterol efflux and HDL-mediated reverse cholesterol transport. Although the precise mechanisms of ABCA1 function are not completely understood, recent data suggest that the ABCA1 pathway regulates vesicular traffic, filipodia formation and lipid microdomains, thereby controlling susceptibility to atherosclerosis. Nuclear hormone receptors including LXR/RXR and PPAR/RXR heterodimers are recognized as direct or indirect regulators of ABCA1 expression and are discussed as potential targets for pharmacological intervention in cardiovascular disease. Future studies clarifying the processes involved in the ABCA1 pathway at the cellular level are expected to identify new and possibly more specific pharmaceutical targets.
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PMID:ATP-binding cassette transporters in macrophages: promising drug targets for treatment of cardiovascular disease. 1213 3

Several ATP-binding cassette (ABC) transporters are critically involved in cholesterol and phospholipid efflux, reverse cholesterol transport, and play an important role in the development of atherosclerosis. Quantification of ABC mRNA is important in studying the regulation of cellular cholesterol homeostasis and mechanisms related to the pathogenesis of atherosclerosis. We have developed a one-step real time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) method for measuring mRNA levels of ABCA1, ABCG1, and ABCA2 in murine tissues using the TaqMan(TM) technology. It has significant methodological benefits when compared to classic Northern blotting or semi-quantitative RT-PCR analysis. Using this method, we found high expression levels of ABCA1 in liver and macrophages, and of ABCG1 in the brain and macrophages. The expression of ABCA1 and ABCG1 were further induced in macrophages loaded with acLDL. In contrast, ABCA2 was expressed exclusively in the brain with low expression levels in the macrophages. This method provides a rapid, highly sensitive, specific, and reproducible quantification of ABC mRNA, and can be performed with nanograms of total RNA sample, thus making it a superior method for studying the regulation of ABC transporters in cholesterol efflux and its role in the pathogenesis of atherosclerosis in murine models.
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PMID:Rapid quantification of murine ABC mRNAs by real time reverse transcriptase-polymerase chain reaction. 1245 81

PURPOSE OF REVIEW This review discusses recent progress in the role of ATP-binding cassette proteins ABCG5 and G8 in dietary sterol absorption, excretion and pathogenesis of cardiovascular disease. RECENT FINDINGS Identification of the genetic defect(s) underlying sitosterolemia has led to a renewed interest in the mechanisms of sterol absorption and biliary excretion. Mutations in ABCG5 (encoding sterolin-1) or ABCG8 (encoding sterolin-2) cause this disease. These proteins are thought to function by preventing dietary noncholesterol sterols from being retained by the body and for cholesterol excretion into bile. SUMMARY Despite improvements in treatments for hypercholesterolemia with cholesterol lowering agents, cardiovascular disease still remains highly prevalent. This has prompted many to consider that molecules other than cholesterol may be better biomarkers for this disease and targeting these more directly may allow us to develop more effective therapies. Ideally, if such a biomarker were also the bioactive molecule that is key to initiating/propagating the atherosclerosis pathogenic pathway, this would allow us to develop an optimal predictor and monitor of the disease process. One source of such molecules could come from our diet, with potential candidates such as noncholesterol sterols, oxysterols, oxidized sterols or some as yet unidentified dietary bioactive molecule. Nature has evolved a protective mechanism by which such molecules are kept out of the body, thereby reducing the negative effects of these compounds. The newly identified sterolin proteins involved in the absorption and excretion of dietary sterols may fit this bill. If so, we would speculate that a better biomarker may be lurking within their substrate specificities.
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PMID:Genetic defenses against noncholesterol sterols. 1286 30

The antiatherogenic effect of high-density lipoprotein (HDL) and its major protein component apolipoprotein A-I (apoA-I) has been largely attributed to their key roles in reverse cholesterol transport (RCT) and cellular cholesterol efflux. Substantial evidence shows that overexpression of human apoA-I reduces atherosclerosis in animal models. However, it is uncertain whether this protection is due to an increase in plasma HDL level or to a local effect in the artery wall. To test the hypothesis that expression of human apoA-I in macrophages can promote RCT in the artery wall, we used a retroviral construct expressing human apoA-I cDNA (MFG-HAI) to transduce ApoE(-/-) bone marrow cells and then transplanted these cells into ApoE(-/-) mice with preexisting atherosclerosis. ApoE(-/-) mice reconstituted with MFG-HAI marrow had a significant reduction (30%) in atherosclerotic lesions in the proximal aorta compared to control mice that received marrow expressing MFG parental virus. Peritoneal macrophages isolated from MFG-HAI mice showed a four- to fivefold increase in mRNA expression levels of both ATP-binding cassette (ABC) A1 and ABCG1 compared to controls. Our data demonstrate that gene transfer-mediated expression of human apoA-I in macrophages can compensate in part for apoE deficiency and delay the progression of atherosclerotic lesions by stimulating ABC-dependent cholesterol efflux and RCT.
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PMID:Macrophage apolipoprotein A-I expression protects against atherosclerosis in ApoE-deficient mice and up-regulates ABC transporters. 1452 30


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