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)

Lp(a) is a major inherited risk factor for premature atherosclerosis. The mechanism of Lp(a) atherogenicity has not been elucidated, but likely involves both its ability to interfere with plasminogen activation and its atherogenic potential as a lipoprotein particle after receptor-mediated uptake. We demonstrate that Lp(a) stimulates production of vascular cell adhesion molecule 1 (VCAM-1) and E-selectin in cultured human coronary artery endothelial cells (HCAEC). This effect resulted from a rise in intracellular free calcium induced by Lp(a) and could be inhibited by the intracellular calcium chelator, BAPTA/AM. The involvement of the LDL and VLDL receptors in Lp(a) activation of HCAEC were ruled out since Lp(a) induction of adhesion molecules was not prevented by an antibody (IgGC7) to the LDL receptor or by receptor-activating protein, an antagonist of ligand binding to the VLDL receptor. Addition of alpha2-macroglobulin as well as treatment with heparinase, chondroitinase ABC, and sodium chlorate did not decrease levels of VCAM-1 and E-selectin stimulated by Lp(a), suggesting that neither the low density lipoprotein receptor-related protein nor cell-surface proteoglycans are involved in Lp(a)-induced adhesion molecule production. Neither does the binding site on HCAEC responsible for adhesion molecule production by Lp(a) appear to involve plasminogen receptors, as levels of VCAM-1 and E-selectin were not significantly decreased by the addition of glu-plasminogen, the lysine analog epsilon-aminocaproic acid, or by trans-4-(aminomethyl)-cyclohexanecarboxymethylic acid (tranexamic acid), which acts by binding to the lysine binding sites carried on the kringle structures in plasminogen. In contrast, recombinant apolipoprotein (a) [r-apo(a)] competed with Lp(a) and attenuated the expression of VCAM-1 and E-selectin. In summary, we have identified a calcium-dependent interaction of Lp(a) with HCAEC capable of inducing potent surface expression of VCAM-1 and E-selectin that does not appear to involve any of the known potential Lp(a) binding sites. Because leukocyte recruitment to the vessel wall appears to represent one of the important early events in atherogenesis, this newly described endothelial cell-activating effect of Lp(a) places it at a crucial juncture in the initiation of atherogenic disease and may lead to a better understanding of the role of Lp(a) in the vascular biology of atherosclerosis.
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PMID:Expression of adhesion molecules by lp(a): a potential novel mechanism for its atherogenicity. 983 67

Aggregated low density lipoprotein (LDL) is taken up by macrophages at enhanced rate, leading to macrophage cholesterol accumulation and foam cell formation. Since macrophages were shown to mediate self aggregation of modified forms of LDL, we sought to study the effect of macrophages on the susceptibility of native LDL to aggregation. Incubation of LDL (100 microg of protein/ml) with J-774A.1 macrophage-like cell line for 18 h at 37 degrees C, led to a 114 and 56% enhanced susceptibility of LDL to aggregation by vortexing and by Bacillus cereus SMase respectively. Macrophage conditioned media (MCMs) that were obtained from J-774A.1 cells also enhanced the susceptibility of LDL to aggregation by vortexing and SMase by 134 and 75% respectively, suggesting the involvement of macrophage secretory products in the enhanced aggregation of LDL. As proteoglycans were shown to be involved in lipoprotein aggregation, we analyzed the possible involvement of macrophage-released proteoglycans in LDL aggregation. Incubation of LDL (100 microg protein/ml) with 25 microg of proteoglycans that were isolated from MCM led to a dose-dependent enhanced susceptibility of LDL to aggregation by vortexing or by SMase by up to 62 and 77% respectively. The stimulatory effect of the MCMs on LDL aggregation was markedly reduced upon MCMs treatment with the glycosaminoglycan hydrolyzing enzyme chondroitinase ABC, chondroitinase AC, but not heparinase. On the contrary, incubation of LDL (100 microg of protein/ml) with increasing concentrations (up to 50 microg/ml) of chondroitin sulfate, or heparan sulfate enhanced the susceptibility of LDL to aggregation by up to 98 or by only 18% respectively, in comparison with non-treated LDL. Since macrophages under atherogenic conditions (cholesterol-loading, cellular lipid peroxidation and activation) demonstrate enhanced secretion of proteoglycans, we finally studied the effect of J-774A.1 macrophages on the susceptibility of native LDL to aggregation under the above atherogenic conditions. Incubation of LDL with cholesterol-loaded macrophages led to a 62% enhanced susceptibility of LDL to undergo aggregation by vortexing, in comparison with LDL that was incubated with non-loaded cells. Macrophage activation with phorbol myristate acetate (5 microM of PMA) also significantly increased cell-mediated aggregation of LDL by 50%, in comparison with non-activated cells. Lipid peroxidized macrophages obtained by cell treatment with either FeSO4 (50 microM), or angiotensin II (10(-7) M) enhanced the susceptibility of LDL to aggregation by 22 or by 39% respectively. These results suggest that under atherogenic conditions, macrophages release proteoglycans, and mainly chondroitin sulfate, which can contribute to cell-mediated formation of aggregated LDL, a potent inducer of macrophage foam cells which are the hallmark of early atherogenesis.
Atherosclerosis 1999 Jan
PMID:Macrophage released proteoglycans are involved in cell-mediated aggregation of LDL. 992 May 6

Lipoprotein interactions with macrophage proteoglycans (PGs) is believed to play an important role in the cellular uptake of lipoproteins and in macrophage cholesterol accumulation. Recently, we have shown the participation of macrophage plasma membrane glycosaminoglycans (GAGs) in the cellular uptake of oxidized LDL (Ox-LDL). The aim of the present study was to identify the specific cell surface proteoglycans involved in this interaction. J-774 A.1 macrophage-like cell line plasma membrane proteoglycans were isolated by anion exchange chromatography from cells that were prelabeled with [35S]sodium sulfate. Using Sepharose 6B chromatography, cell surface major proteoglycans were identified as chondroitin sulfate (CS) proteoglycans (77%) and heparan sulfate (HS) proteoglycans (23%). Binding rates of these 35S-labeled proteoglycans to Ox-LDL and to native LDL were analyzed by their ability to bind lipoproteins coupled to a CnBr-activated Sepharose CL-4B chromatography. Of the total labeled cell surface proteoglycans added to the column, 57% were bound to the Sepharose-coupled Ox-LDL, whereas 73% of the cell surface proteoglycans were bound to the Sepharose-coupled native LDL. Binding of the plasma membrane macrophage 35S-labeled proteoglycans to Ox-LDL was inhibited by adding increasing concentrations of non-labeled chondroitin sulfate, or by pretreatment of the 35S-labeled proteoglycans fraction with chondroitinase ABC. In contrast, neither the addition of non-labeled heparan sulfate, nor pretreatment of the labeled proteoglycans fraction with heparinase III, had any significant effect on proteoglycan binding to Ox-LDL. These findings were further supported by using mutant cells characterized by specific glycosaminoglycan deficiencies. Ox-LDL binding and degradation by mutant 745 CHO cells which are characterized by a deficiency in both heparan sulfate and chondroitin sulfate, was decreased by 28 and 27% respectively, compared to the binding of Ox-LDL to the wild-type CHO cells. Ox-LDL binding and degradation by mutant 677 CHO cells, which lack heparan sulfate but have increased levels of chondroitin sulfate, however, was found to be increased by 29 and 19%, respectively, compared to Ox-LDL binding to the wild-type CHO cells. Finally, analysis of the cell surface proteoglycans in macrophages that were subjected to oxidative stress, by their preincubation with angiotensin II, exhibited a 51-59% increase in their cell surface proteoglycan content, with a major effect on chondroitin sulfate proteoglycans. The present study thus demonstrated that Ox-LDL can specifically bind to macrophage surface chondroitin sulfate proteoglycans, and the macrophage content of this proteoglycan is increased under oxidative stress. The interaction between macrophage chondroitin sulfate proteoglycans and Ox-LDL can contribute to enhanced uptake of Ox-LDL with the formation of cholesterol-loaded foam cells, and accelerated atherosclerosis.
Atherosclerosis 2000 Mar
PMID:Macrophage plasma membrane chondroitin sulfate proteoglycan binds oxidized low-density lipoprotein. 1070 9

Aggregated low-density lipoprotein (LDL) was shown to be present in the atherosclerotic lesion, but the mechanism responsible for its formation in vivo is not known yet. To find out whether LDL aggregation occurs in the arterial wall during atherogenesis, LDLs were extracted from the aortas of apolipoprotein E-deficient (E(0)) mice during their aging (and the development of atherosclerosis), and were analyzed for their aggregation states, in comparison to LDLs isolated from aortas of control mice. LDL isolated from aortas of E(0) mice was already aggregated at 1 month of age and its aggregation state substantially increased with age, with 3-fold elevation at 6 months of age compared to younger, 1-month-old, mice. Only minimal aggregation could be detected in LDL derived from control mice. Electron microscopy examination revealed that LDL particles from aortas of the E(0) mice were heterogeneous in their size, ranging between 20 and 300 nm. The mouse aortic LDL contained proteoglycans (PGs) and their content increased with the age of the mice, with about 2-fold higher levels than those found in LDLs derived from aortas of control mice. Macrophage-released PGs were previously demonstrated to enhance LDL aggregation in vitro. However, their involvement in LDL aggregation in vivo has not been studied yet. Thus, we next studied the effect of arterial macrophage-released PGs on the susceptibility of plasma LDL to aggregation by Bacillus cereus sphingomyelinase (SMase). Foam cell macrophages were isolated from aortas of the atherosclerotic E(0) mice at 6 months of age and were found to be loaded with cholesterol and to contain oxidized lipids. To analyze the effect of macrophage-released PGs on LDL aggregation, PGs were prelabeled by cell incubation with [35S]sulfate, followed by incubation of macrophage-released PGs with E(0) mouse plasma LDL (200 microg protein/ml) for 1 h at 37 degrees C. [35S]Sulfated PGs were found to be LDL-associated and the susceptibility of PG-associated LDL to aggregation by SMase was increased by up to 45% in comparison to control LDL. Similar results demonstrating the involvement of PGs in LDL aggregation were obtained upon incubation of LDL with increasing concentrations of PGs that were isolated from the entire aorta of E(o) mice (rather than the isolated macrophages). The stimulatory effect of macrophage-released PGs on LDL aggregation was markedly reduced when the PGs were pretreated with the glycosaminoglycan-hydrolyzing enzymes, chondroitinase ABC or chondroitinase AC, and to a much lesser extent with heparinase. We thus conclude that macrophage-released chondroitin sulfate PG can contribute to the formation of atherogenic aggregated LDL in the arterial wall.
Atherosclerosis 2000 May
PMID:Macrophage-released proteoglycans enhance LDL aggregation: studies in aorta from apolipoprotein E-deficient mice. 1078 39

In healthy individuals, acute changes in cholesterol intake produce modest changes in plasma cholesterol levels. A striking exception occurs in sitosterolemia, an autosomal recessive disorder characterized by increased intestinal absorption and decreased biliary excretion of dietary sterols, hypercholesterolemia, and premature coronary atherosclerosis. We identified seven different mutations in two adjacent, oppositely oriented genes that encode new members of the adenosine triphosphate (ATP)-binding cassette (ABC) transporter family (six mutations in ABCG8 and one in ABCG5) in nine patients with sitosterolemia. The two genes are expressed at highest levels in liver and intestine and, in mice, cholesterol feeding up-regulates expressions of both genes. These data suggest that ABCG5 and ABCG8 normally cooperate to limit intestinal absorption and to promote biliary excretion of sterols, and that mutated forms of these transporters predispose to sterol accumulation and atherosclerosis.
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PMID:Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters. 1118 92

The volumetric density of vascular smooth muscle cells (VSMC) in the proximal vertebral artery was investigated. In order to identify VSMC, paraffin-embedded sections of the proximal vertebral artery, obtained from autopsy specimens, were immunostained for smooth muscle alpha-actin by a modified ABC-technique. The 63 autopsy specimens, including 35 males and 28 females, covered the entire range from 2 months to 85 years. The volumetric density of alpha-actin positive VSMC in the tunica media was morphometrically assayed by the point-counting method. It is important to note that the morphometrical evaluation was performed on arteries obtained from autopsy specimens of the years 1953/54, a post-war time characterized in Germany by low fat diet as compared to the present-day nutrition of most industrial nations. Probably due to their origin, the vertebral arteries showed almost no atheroma. As the main purpose of this study was to find out about the atherosclerosis-independent process of aging, these arteries seemed particularly suitable. The evaluation showed a strictly age-dependent leiomuscular atrophy which became morphometrically evident in early adulthood. The average degree of regression was measured at 0.62% per year. These results may justify the conclusion that the leiomuscular atrophy of the media represents a primary age-related process and does not in any way result as a secondary event from an atheromatous transformation of the intima.
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PMID:Age-dependent leiomuscular atrophy in vertebral arteries of individuals under low fat diet. 1112 48

The molecular mechanisms regulating the amount of dietary cholesterol retained by the body, as well as the body's ability to exclude other dietary sterols selectively, are poorly understood. An average Western diet will contain approximately 250-500 mg of dietary cholesterol and approximately 200-400 mg of non-cholesterol sterols, of which plant sterols are the major constituents. Approximately 50-60% of dietary cholesterol is absorbed and retained by the normal human body, but less than 1% of the non-cholesterol sterols are retained. There thus exists a subtle mechanism that allows the body to distinguish between cholesterol and non-cholesterol sterols. In sitosterolemia, a rare autosomal recessive disorder, affected individuals hyperabsorb and retain not only cholesterol but also all other sterols, including plant and shellfish sterols from the intestine. Consequently, patients with this disease have very high levels of plant sterols in the plasma, and develop tendon and tuberous xanthomas, accelerated atherosclerosis, and premature coronary artery disease. The STSL locus has been mapped to human chromosome 2p21. Mutations in two tandem ABC genes, ABCG5 and ABCG8, encoding sterolin-1 and -2, respectively, are now known to be mutant in sitosterolemia. The identification of these genes should now lead to a better understanding of the molecular mechanism(s) governing the highly selective absorption and retention of cholesterol by the body. Indeed, it is the very existence of this disease that has given credence to the hypothesis that there is a molecular pathway that regulates dietary cholesterol absorption and sterol excretion by the body.
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PMID:Genetic basis of sitosterolemia. 1126 85

The ATP-binding cassette transporter, ABCA1, is a member of the ABC superfamily of proteins involved in the active transport of substrates across cellular membranes. Recent studies have implicated mutations in ABCA1 as the cause of Tangier disease (TD) and familial hypoalphalipoproteinemia (FHA). To evaluate the molecular basis of low high density lipoprotein (HDL) in a family with premature coronary artery disease, single strand conformational polymorphism analysis was performed for all coding regions and splice site junctions of ABCA1 with the genomic DNA of the proband. The proband and affected individuals were heterozygotes for C254T with proline converted to leucine (P85L). This mutation was not identified in over 400 chromosomes of healthy subjects. In the FHA kindred, family members heterozygous for the ABCA1 variant also exhibited corresponding low levels of HDL cholesterol. These data confirm recent data that a single defective allele in ABCA1 may be associated with reduced HDL cholesterol and FHA.
Atherosclerosis 2002 Oct
PMID:ABCA1(Alabama): a novel variant associated with HDL deficiency and premature coronary artery disease. 1292 88

The family of adenosine triphosphate (ATP)-binding cassette (ABC) transporters is the largest gene family known. While some ABC transporters translocate single substances across membranes with high specificity, others transport a wide variety of different lipophilic compounds. They are responsible for many physiological processes and are also implicated in a number of diseases. The present review focuses on ABC transporter genes which are involved in ageing and age-related diseases. Expression of ABCB1 (MDR1, P-glycoprotein) increases with age in CD4(+) and CD8(+) T-lymphocytes indicating that P-glycoprotein may be involved in the secretion of cytokines, growth factors, and cytotoxic molecules. As T cells in aged individuals are hyporesponsive leading to a reduced immunodefence capability, a role of ABCB1 in age-related immunological processes is presumed. The ABCA1 (ABC1) gene product translocates intracellular cholesterol and phospholipids out of macrophages. Genetic aberrations in ABCA1 cause perturbations in lipoprotein metabolism and contribute to atherosclerosis. ABCA4 (ABCR) represents a retina-specific ABC transporter expressed in rod photoreceptor cells. The ABCA4 gene product translocates retinyl-derivatives. Mutations in the ABCA4 gene contribute to age-related macular degeneration. Polymorphisms in the sulfonylurea receptor gene (ABCC8, SUR1) are associated with non-insulin-dependent diabetes mellitus (NIDDM). Sulfonylureas inhibit potassium conductance and are used to treat NIDDM by stimulation of insulin secretion across ATP-sensitive potassium channels in pancreatic beta-cell membranes. Possible diagnostic and therapeutic implications of ABC transporters for age-related diseases are discussed.
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PMID:Adenosine triphosphate-binding cassette transporter genes in ageing and age-related diseases. 1243 93

Peroxisome proliferator-activated receptors (PPARs) play an important role in vascular events during progression of atherosclerosis, associated with lipid metabolism, inflammatory response and others. To clarify relationships between the expression of PPARs subtypes and regression, we studied mRNA expression of PPARs subtypes with reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry, especially in centrally depressed atherosclerotic plaques (depressed plaque) in the aortas of elderly patients, and proposed morphological feature of atherosclerotic regression. Samples were separated from the depressed plaque, atheromatous plaque, and diffuse intimal thickening (DIT) in the aortas of elderly patients at autopsy and they were analyzed for RT-PCR. The depressed plaques obtained were divided into two parts: depressed area and surrounding elevated area. Total RNA was prepared, using the TRIzol Reagent, and was reverse transcribed using random hexamer primers and Thermoscript kit for RT-PCR. Immunohistochemical analysis was processed for mouse anti-PPAR gamma antibody, detected by the ABC method. 1) Decreased foam cells were found in the depressed area than in the surrounding elevated area of the depressed plaque. These foam cells were immunohistochemically positive for HAM56 and strong reactivities for PPAR gamma were found in the nuclei of macrophage-derived foam cells. PPAR gamma was also detected in the nuclei of endothelial cells and smooth muscle cells. 2) Expressions of PPAR alpha and PPAR gamma were found in the depressed plaques with RT-PCR. These expressions were found both in the depressed area and the surrounding elevated area without significant differences. 3) PPAR gamma mRNA expression both in the depressed area and the surrounding elevated area, was greater than in DIT, and was less than in the atheromatous plaque. 4) Expression of PPAR gamma mRNA was intense and increased in the surrounding elevated area than in the depressed area. 5) A significant increase of PPAR gamma expression was found in the atheromatous plaque than in the DIT. 6) There was no significant difference of PPAR alpha mRNA expression between the depressed area and the surrounding elevated area. The depressed plaque has been considered to be a morphological characteristic of regression in recent studies. Expression of mRNA for PPARs was detected in the depressed plaque as well as the atheromatous plaque, furthermore, there were different expressions and intensity of PPARs between the depressed area and the surrounding elevated area of the depressed plaque. These findings suggest that the expression of PPARs may be involved not only in the progression of atherosclerosis but also in regression.
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PMID:[Atherosclerotic regression in the aortas of elderly. (4). Expression of peroxisome proliferator-activated receptors with references of centrally depressed atherosclerotic plaque]. 1499 25


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