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

The mechanisms responsible for the inverse relationship between plasma high-density lipoprotein (HDL) levels and atherosclerotic cardiovascular disease are poorly understood. The ATP-binding cassette transporter A1 (ABCA1) mediates efflux of cellular cholesterol to lipid-poor apolipoproteins but not to HDL particles that constitute the bulk of plasma HDL. We show that two ABC transporters of unknown function, ABCG1 and ABCG4, mediate isotopic and net mass efflux of cellular cholesterol to HDL. In transfected 293 cells, ABCG1 and ABCG4 stimulate cholesterol efflux to both smaller (HDL-3) and larger (HDL-2) subclasses but not to lipid-poor apoA-I. Treatment of macrophages with an liver X receptor activator results in up-regulation of ABCG1 and increases cholesterol efflux to HDL. RNA interference reduced the expression of ABCG1 in liver X receptor-activated macrophages and caused a parallel decrease in cholesterol efflux to HDL. These studies indicate that ABCG1 and ABCG4 promote cholesterol efflux from cells to HDL. ABCG1 is highly expressed in macrophages and probably mediates cholesterol efflux from macrophage foam cells to the major HDL fractions, providing a mechanism to explain the relationship between HDL levels and atherosclerosis risk.
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PMID:ATP-binding cassette transporters G1 and G4 mediate cellular cholesterol efflux to high-density lipoproteins. 1521 Sep 59

The accumulation of extracellular matrix components such as proteoglycans is a hallmark of an atherosclerotic lesion. A large heparan sulfate proteoglycan, perlecan, dramatically increases in the advanced lesion, and vascular smooth muscle cells are the cell type responsible for the accumulation. In this study, we investigated the effects of thrombin on the proteoglycan synthesis in cultured human coronary smooth muscle cells to determine the interrelationship between the accumulation of proteoglycans and the procoagulant state of blood in atherosclerosis. The cells were metabolically labeled with [(35)S]sulfate or (35)S-labeled amino acids in the presence of thrombin, and the labeled proteoglycans were characterized by Sepharose CL-4B molecular sieve chromatography and DEAE-Sephacel ion-exchange chromatography. The glycosaminoglycan M(r) and composition were analyzed by Sepharose CL-6B chromatography, and the core protein M(r) was determined by SDS-polyacrylamide gel electrophoresis before and after digestion with chondroitinase ABC or papain. The results indicate that thrombin increases the cell layer-associated heparan sulfate proteoglycan with a core protein size of approximately 400 kDa without any change in the length of the glycosaminoglycan chains when the cell density is high. The heparan sulfate proteoglycan was identified as perlecan by Western blot analysis. In addition, quantitative reverse transcription-polymerase chain reaction showed that thrombin elevated the steady-state level of perlecan mRNA but not that of versican, decorin, and syndecan-1 mRNAs, although that of biglycan mRNA was moderately elevated. Furthermore, the percentage of disaccharide units that compose perlecan heparan sulfate chains remained unaffected by thrombin. Therefore, it is suggested that thrombin induces the perlecan core protein synthesis without influencing the formation of the heparan sulfate chains in human coronary smooth muscle cells at a high cell density. The regulation of proteoglycan synthesis by thrombin may be involved in the accumulation of perlecan in advanced lesions of atherosclerosis.
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PMID:Induction of synthesis of a large heparan sulfate proteoglycan, perlecan, by thrombin in cultured human coronary smooth muscle cells. 1571 25

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

Atherosclerosis is a disease of blood vessel walls that is thought to be initiated as a reaction of insults to the endothelium. The complex sequence of cellular events that begins with focal inflammation leads to the accumulation of leukocytes in the subendothelial layer and unrestricted uptake of oxidized lipoproteins by macrophages and smooth muscle cells, leading to foam cell formation. Vascular endothelial cells do not undergo the foam cell transformation and do not accumulate cholesterol in atherosclerotic plaques to the same extent as macrophages or smooth muscle cells. However, vascular endothelial cells express receptors for oxidized lipoproteins, and have the biochemical pathways for sterol synthesis and receptor-mediated endocytosis of lipoproteins. Data from the authors' laboratory show that high density lipoproteins but not lipid-free apolipoprotein A-I promote cellular cholesterol efflux in human umbilical vascular endothelial cells and human aortic endothelial cells. Gene expression microarrays were used to examine the differential expression of genes after cholesterol loading. While sterol regulatory element-binding protein-sensitive genes were downregulated, the authors identified a novel transporter, the ATP-binding cassette G1 (ABCG1) to be highly expressed in response to both cellular cholesterol loading and stimulation with the liver X receptor agonist 22-hydroxycholesterol. The ABCA1 gene and protein, the major modulator of cellular cholesterol efflux in macrophages and in peripheral and hepatic tissues, are only weakly expressed in human umbilical vascular endothelial cells and human aortic endothelial cells. These data suggest that endothelial cells maintain cholesterol homeostasis by downregulating cholesterol synthesis and low density lipoprotein receptors and by a cellular cholesterol efflux mechanism onto low-affinity but high-capacity high density lipoproteins. The role of ABC-type transporters, including ABCG1, requires further examination.
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PMID:Cellular cholesterol homeostasis in vascular endothelial cells. 1649 11

Foam cell formation due to excessive accumulation of cholesterol by macrophages is a pathological hallmark of atherosclerosis. Macrophages cannot limit the uptake of cholesterol and therefore depend on cholesterol efflux pathways for preventing their transformation into foam cells. Several ABC-transporters, including ABCA1 and ABCG1, facilitate the efflux of cholesterol from macrophages. These transporters, however, also affect membrane lipid asymmetry which may have important implications for cellular endocytotic pathways. We propose that in addition to the generally accepted role of these ABC-transporters in the prevention of foam cell formation by induction of cholesterol efflux from macrophages, they also influence the macrophage endocytotic uptake.
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PMID:Regulation of cholesterol homeostasis in macrophages and consequences for atherosclerotic lesion development. 1693 83

Proteoglycans accumulate in lesions of atherosclerosis but little is known as to which factors regulate the synthesis of these molecules. Interleukin-1beta (IL-1beta) is a cytokine involved in vascular lesion development but it is not clear whether it has specific effects on proteoglycan synthesis by arterial smooth muscle cells (ASMC). Monkey ASMC were treated with IL-1beta and proteoglycan synthesis assessed using [(35)S]-sulfate and [(35)S]-Trans amino acid labeling. Four prominent size populations of proteoglycans, as determined by SDS-PAGE gradient gel electrophoresis, were observed in the culture medium and identified as versican, biglycan, decorin, and an unknown population that migrated to the gel interface. IL-1beta treatment decreased significantly the synthesis of versican, while increasing the synthesis of decorin, but having no effect on biglycan synthesis. Northern blot analyses confirmed this selective effect on versican and decorin mRNA transcripts. Nuclear run-on and RNA inhibition studies showed that decreased mRNA for versican was due to increased mRNA degradation and not to changes in transcription. In addition, IL-1beta increased the synthesis of the population of proteoglycans that separated at the SDS-PAGE gel interface. Chondroitinase ABC lyase digestion of this population revealed a complex of proteins composed of versican (350 kDa), an unidentified protein (215 kDa), and a 23 kDa protein identified by sequence analyses as serglycin. These data demonstrate that IL-1beta selectively downregulates versican synthesis by ASMC, while positively regulating the synthesis of other proteoglycans.
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PMID:Interleukin-1beta selectively decreases the synthesis of versican by arterial smooth muscle cells. 1722 75

Adipocytokines are a subset of cytokines produced by adipose tissue and are associated with risk of type II diabetes and atherosclerosis. Levels of adipocytokines differ between Black and White Americans, even after adjustment for differences in adiposity, diseases associated with adipocytokines including type 2 diabetes and cardiovascular disease, and general socioeconomic status indicators such as income. We used a series of ancestry informative markers to estimate genetic ancestry in a population-based study of older Black Americans, and examined the association between genetic ancestry and adipocytokines and soluble receptors to help determine which of these may be most amenable to admixture mapping. We typed 35 ancestry informative markers in 1,241 self-reported Black Americans with available DNA from the Health, Aging, and Body Composition (Health ABC) study with available DNA and used a maximum likelihood approach to estimate percent European ancestry. We used linear regression models to determine the association between these adipocytokines and percent ancestry, and staged models to examine whether adiposity or other measures affected the associations of genetic ancestry and adipocytokines. Mean European ancestry was 22.3+/-15.9%. In multivariate adjusted models, the strongest associations observed were between higher European ancestry and interleukin-6 soluble receptor (IL-6 SR), C-reactive protein (CRP), and adiponectin levels, with interleukin-2 soluble receptor (IL-2 SR) and soluble tumor necrosis factor receptor II (TNF-alpha SR II) also showing more modest but significant associations. The association with adiponectin became stronger after adjustment for adiposity. These novel findings suggest that admixture mapping may identify genetic factors influencing the levels of IL-6 SR, CRP, IL-2 SR, and adiponectin.
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PMID:Genetic admixture, adipocytokines, and adiposity in Black Americans: the Health, Aging, and Body Composition study. 1739 Jan 49

Recent findings from several groups demonstrate that ABC-A1 participates in the pathogenesis of the metabolic syndrome and type 2 diabetes. A variant of the ABC-A1 gene (R230C) is associated with the metabolic syndrome and its co-morbidities in Mexicans. Its presence is associated with an increased risk for obesity, the metabolic syndrome and type 2 diabetes. R230C is found exclusively in Amerindian and Amerindian-derived populations. Moreover, animal models confirm the participation of ABC-A1 in the pathogenesis of diabetes. Mice lacking AbcA1 specifically in beta cells had glucose intolerance at 8 weeks of age. The absence of ABC-A1 led to cholesterol accumulation within the beta cell plasma membrane, suggesting that cholesterol may play a role in the insulin secretory pathway. In conclusion, ABC-A1 may be more than a determinant of HDL-cholesterol. It may provide a link between components of the metabolic syndrome and atherosclerosis.
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PMID:The ATP-binding cassette transporter subfamily A member 1 (ABC-A1) and type 2 diabetes: an association beyond HDL cholesterol. 1822 Jun 85

Persistently low white blood cell count (WBC) and neutrophil count is a well-described phenomenon in persons of African ancestry, whose etiology remains unknown. We recently used admixture mapping to identify an approximately 1-megabase region on chromosome 1, where ancestry status (African or European) almost entirely accounted for the difference in WBC between African Americans and European Americans. To identify the specific genetic change responsible for this association, we analyzed genotype and phenotype data from 6,005 African Americans from the Jackson Heart Study (JHS), the Health, Aging and Body Composition (Health ABC) Study, and the Atherosclerosis Risk in Communities (ARIC) Study. We demonstrate that the causal variant must be at least 91% different in frequency between West Africans and European Americans. An excellent candidate is the Duffy Null polymorphism (SNP rs2814778 at chromosome 1q23.2), which is the only polymorphism in the region known to be so differentiated in frequency and is already known to protect against Plasmodium vivax malaria. We confirm that rs2814778 is predictive of WBC and neutrophil count in African Americans above beyond the previously described admixture association (P = 3.8 x 10(-5)), establishing a novel phenotype for this genetic variant.
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PMID:Reduced neutrophil count in people of African descent is due to a regulatory variant in the Duffy antigen receptor for chemokines gene. 1918 Feb 33

The huge improvement in the therapeutic arsenal for HIV infection has led to HIV becoming a chronic disease. Like us, our patients are aging and their life expectancy is close to that of the general population. Consequently, we need safe, easily administered drugs with interactions that can be controlled and the least possible impact on highly prevalent comorbidities such as atherosclerosis or coinfection with hepatotropic viruses. Drugs should fit the patient's lifestyle without affecting quality of life and, above all, be free of effects leading to stigma, such as lipoatrophy, a major concern for most recently diagnosed patients. The choice of the two nucleoside analogue reverse transcriptase inhibitors used at the start of antiretroviral therapy should be based on careful evaluation of the abundant data accumulated on all these determining factors which are heralding a new era in the control of HIV infection. Thus, in this scenario, thymidine analogues have been relegated to alternative use. Fixeddose combinations of tenofovir and emtricitabine (TDF/FTC) or abacavir and lamivudine (ABC/3TC) are the backbone of choice when initiating antiretroviral therapy. Direct comparative data are still scarce but suggest similar virological efficacy, with highly preliminary data suggesting some disadvantages associated with the use of ABC/3TC. After excluding patients at risk of hypersensitivity to ABC, both combinations are well tolerated, but TDF/FTC is associated with a better lipid profile. Recent data from the Data Collection on Adverse Events of Anti-HIV drugs (DAD) study show an unexpected association of ABC with increased cardiovascular risk and thus more detailed studies are required.
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PMID:[Are all analogue combinations equal?]. 1919 37


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