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

1. In vivo and in vitro gene-manipulated models were used to study the metabolism of chylomicron remnants. Transgenic mice expressing human apolipoprotein (Apo) A1 or E4, gene knockout mice deficient in ApoE or low density lipoprotein (LDL) receptors and antisense gene inhibition in HepG2 cells were used to evaluate the effect of gene manipulations on the metabolism of chylomicron remnants. 2. Mice transgenic for human ApoE4 showed accelerated clearance of chylomicron-like emulsions when animals were fed a low-fat diet. When challenged by a high-fat diet, remnant clearance in ApoE4 transgenic mice was delayed, as in normal or non-transgenic controls. However, unlike normal nontransgenic controls, in ApoE4 transgenic mice high density lipoprotein (HDL)-cholesterol levels remained high after high-fat feeding, which probably protected the animals from the development of atherosclerosis. In contrast, clearance of chylomicron-like lipid emulsions was not affected by the over-expression of human ApoAI in transgenic mice. 3. Gene knock-out mice deficient in ApoE or deficient in the LDL receptor were used to show that ApoE and LDL receptors are both essential for the normal, fast catabolism of chylomicron remnants by the liver. In the absence of the LDL receptor, an alternative ApoE-dependent pathway operates to clear chylomicrons from the plasma, with significantly delayed catabolism. 4. Antisense gene inhibition techniques were used to suppress the expression of syndecan, a core protein of heparan sulfate proteoglycan, in HepG2 cells. Remnant uptake in cells transfected with the antisense oligodeoxynucleotide complementary to a 20 nucleotide sequence upstream of the initiation site of syndecan cDNA markedly reduced the uptake of chylomicron remnant.
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PMID:Use of gene-manipulated models to study the physiology of lipid transport. 913 Dec 98

Enrichment of proteoglycans is prominent in early atherogenesis, contributing not only to SMC migration and proliferation, but also to low density lipoprotein retention. A family of integral cell membrane proteoglycans termed syndecans has recently been recognized. Among syndecans, syndecan-1, the first isolated member, has received most research attention. In this study, we examined the expression of syndecan-1 in rabbit aorta and aortic neointima, developed in response to a balloon catheter-induced de-endothelialization. The tissues were processed for Northern blot analysis, in situ hybridization, immunohistochemical staining and immunoblotting. Our results indicate that in normal aorta, the signal for syndecan-1 is weak. However, arterial injury induces syndecan-1 expression at both mRNA and protein levels. The presence of syndecan-1 in the neointimal tissue is persistent, prominent even at the 12th week after injury. Syndecan positive cells are distributed in the whole layer of the neointima, but are not visible in the underlying media. The presence of syndecan-1 in arterial neointima suggests a novel means of mediating interactions between neointimal cells and various agents, including extracellular matrix components, growth factors and lipoproteins.
Atherosclerosis 1997 Jun
PMID:Expression of syndecan-1 in rabbit neointima following de-endothelialization by a balloon catheter. 919 66

Inflammation may contribute to the pathogenesis of atherosclerosis. On the basis of previous reports that human atherosclerotic lesions contain alpha-defensins, a class of cationic proteins released by activated neutrophils, the study was designed to ask whether defensins modulate the binding and catabolism of low-density lipoprotein (LDL) by human vascular cells. The results of the study demonstrated that defensin stimulated the binding of (125)I-LDL to cultured human umbilical vein endothelial cells, smooth muscle cells, and fibroblasts approximately 5-fold in a dose-dependent and saturable manner. Defensin and LDL formed stable complexes in solution and on cell surfaces. Stimulation of LDL binding by defensin was not inhibited by antibodies against the LDL-receptor (LDL-R), or by recombinant receptor-associated protein, which blocks binding of ligands to the alpha(2)-macroglobulin receptor/LDL-R-related protein and other LDL-R family members. Furthermore, defensin stimulated the binding, endocytosis, and degradation of LDL by fibroblasts lacking LDL-R. Stimulation of LDL degradation by defensin was inhibited approximately 75% by low concentrations of heparin (0.2 units/mL) and was similarly reduced in CHO cells lacking heparan-sulfate-containing proteoglycans. The effect of defensin was substantially increased in cells overexpressing the core protein of the syndecan-1 heparan sulfate proteoglycan. The alpha-defensins released from activated neutrophils may provide a link between inflammation and atherosclerosis by changing the pattern of LDL catabolism from LDL-R to the less efficient LDL-R-independent, proteoglycan-dependent pathway. (Blood. 2000;96:1393-1398)
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PMID:The alpha-defensins stimulate proteoglycan-dependent catabolism of low-density lipoprotein by vascular cells: a new class of inflammatory apolipoprotein and a possible contributor to atherogenesis. 1094 83

Phenytoin (PHT) increases high density lipoprotein cholesterol (HDL-C) and reduces coronary artery disease mortality in humans. We report the results of PHT treatment on atherosclerosis susceptibility and lipid profile in four different types of mouse: control C57BL/6 mice and cholesteryl ester transfer protein transgenic mice as models of fatty streak, and LDL receptor-deficient mice and apolipoprotein E-deficient mice as models of mature atherosclerosis. Each mouse type was fed an appropriate diet to induce atherosclerosis and prevent liver toxicity. PHT treatment demonstrated a protective effect in all models. Reduction in aortic atherosclerotic area by PHT treatment was more evident in early atherosclerosis (2.3-fold) than in mature atherosclerosis (decreases of 40 and 23%, respectively, but only in mice in the upper 50% percentile of plasma PHT concentration). Atherosclerosis prevention was not concomitant with a consistent increase in HDL-C or any other protective change in the lipid profile. Different analyses of potential antiatherogenic HDL functions did not provide additional information. Microarray liver gene expression analyses identified a potential atheroprotective mechanism characterized by decreased expression of syndecan-4, RhoA2, double LIM protein-1, zeta-chain-associated protein kinase-70 and interleukin 6 receptor-alpha. However, to demonstrate that these changes are part of a PHT-antiatherogenic effect, they will need to be found also in arteries, maintained at protein level and proved to be causal rather than reactive.
Atherosclerosis 2004 Jun
PMID:Phenytoin treatment reduces atherosclerosis in mice through mechanisms independent of plasma HDL-cholesterol concentration. 1513 57

Syndecans, a family of cell surface heparan sulfate (HS) containing proteoglycans (PGs), are known regulators of many biological processes including inhibition of smooth muscle cell (SMC) proliferation. Cultured arterial SMCs from atherosclerosis-susceptible White Carneau (WC) pigeons have increased proliferation rates and significant reductions in total cell-surface HS relative to atherosclerosis-resistant Show Racer (SR) SMC. Using a specific syndecan-4 cDNA, 1.5- to 2.0-fold reductions in gene expression were observed in WC SMC compared to SR SMC. Immunolocalization studies demonstrated reduced cell surface syndecan-4 protein in WC cells. Gene induction demonstrated that the reduction in syndecan-4 expression in WC cells was not due to reduced mRNA stability. Studies using cycloheximide to superinduce gene expression indicated transcriptional suppression of syndecan-4 in WC cells. The results suggest that reduced cell surface HS PG in WC arterial SMC can be explained, in part, by reductions in syndecan-4 gene expression. Differential transcriptional regulation of syndecan-4 in WC and SR cells provides a system to explore regulation of the syndecan-4 gene as well as the potential mechanisms by which syndecan-4 can exert a specific antiproliferative effect.
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PMID:Reduced syndecan-4 expression in arterial smooth muscle cells with enhanced proliferation. 1559 55

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

It has been established that syndecan-1 is an important modulator of events relevant to acute tissue repair and chronic injury responses. The current studies were designed to examine syndecan-1 expression during atherosclerotic lesion formation and whether angiotensin II influences syndecan-1 expression in macrophages. ApoE knockout mice maintained on an atherogenic diet were treated for 8 weeks with an infusion of angiotensin II to induce atherosclerosis. Immunohistochemistry was employed to characterize the expression of syndecan-1 in atherosclerotic lesions. Quantitative real-time PCR (QRTPCR) was used to define the role of angiotensin II and responsible signaling pathways involved syndecan-1 expression in RAW264.7 murine macrophages. Protein expression and shedding were characterized by fluorescence activated cell sorting (FACS) and slot blot analysis. Syndecan-1 was abundantly expressed in macrophages located within early atherosclerotic lesions. Accordingly, we hypothesized that angiotensin II regulates syndecan-1 expression in macrophages. A time- and dose-dependent study was performed in RAW264.7 macrophages. QRTPCR demonstrated maximum syndecan-1 mRNA up-regulation at 6 h after 500 nM AgII stimulation (threefold; P < 0.05). Through administration of specific inhibitors, we established that ERK/MAPK, PI3K and JNK signaling pathways mediated this effect. FACS and slot blot analyses demonstrated that cAMP induced posttranscriptional syndecan-1 protein expression in a dose-dependent manner with or without initial angiotensin II stimulation. In particular, angiotensin II induced an increase in cell surface syndecan-1 (mean fluorescence intensity: 147 +/- 5.7 vs. 176 +/- 4.8; P < 0.05; n = 3) and accelerated syndecan-1 shedding. Angiotensin II is a potent regulator of syndecan-1 expression in atherosclerotic lesions via a specific effect on macrophages that is mediated by ERK/MAPK, PI3K, and JNK signaling pathways.
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PMID:Decoupled syndecan 1 mRNA and protein expression is differentially regulated by angiotensin II in macrophages. 1807 60

Elevated plasma triglyceride levels represent a risk factor for premature atherosclerosis. In mice, accumulation of triglyceride-rich lipoproteins can occur if sulfation of heparan sulfate in hepatocytes is diminished, as this alters hepatic lipoprotein clearance via heparan sulfate proteoglycans (HSPGs). However, the relevant HSPG has not been determined. In this study, we found by RT-PCR analysis that mouse hepatocytes expressed the membrane proteoglycans syndecan-1, -2, and -4 and glypican-1 and -4. Analysis of available proteoglycan-deficient mice showed that only syndecan-1 mutants (Sdc1-/- mice) accumulated plasma triglycerides. Sdc1-/- mice also exhibited prolonged circulation of injected human VLDL and intestinally derived chylomicrons. We found that mice lacking both syndecan-1 and hepatocyte heparan sulfate did not display accentuated triglyceride accumulation compared with single mutants, suggesting that syndecan-1 is the primary HSPG mediating hepatic triglyceride clearance. Immunoelectron microscopy showed that syndecan-1 was expressed specifically on the microvilli of hepatocyte basal membranes, facing the space of Disse, where lipoprotein uptake occurs. Abundant syndecan-1 on wild-type murine hepatocytes exhibited saturable binding of VLDL and inhibition by heparin and facilitated degradation of VLDL. Furthermore, adenovirus-encoded syndecan-1 restored binding, uptake, and degradation of VLDL in isolated Sdc1-/- hepatocytes and the lipoprotein clearance defect in Sdc1-/- mice. These findings provide the first in vivo genetic evidence that syndecan-1 is the primary hepatocyte HSPG receptor mediating the clearance of both hepatic and intestinally derived triglyceride-rich lipoproteins.
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PMID:Syndecan-1 is the primary heparan sulfate proteoglycan mediating hepatic clearance of triglyceride-rich lipoproteins in mice. 1980 13

Hypertriglyceridemia, characterized by the accumulation of triglyceride-rich lipoproteins in the blood, affects 10-20% of the population in western countries and increases the risk of atherosclerosis, coronary artery disease, and pancreatitis. The etiology of hypertriglyceridemia is complex, and much interest exists in identifying and characterizing the biological and environmental factors that affect the synthesis and turnover of plasma triglycerides. Genetic studies in mice have recently identified that heparan sulfate proteoglycans are a class of receptors that mediate the clearance of triglyceride-rich lipoproteins in the liver. Heparan sulfate proteoglycans are expressed by endothelial cells that line the hepatic sinusoids and the underlying hepatocytes, and are present in the perisinusoidal space (space of Disse). This chapter discusses the dependence of lipoprotein binding on heparan sulfate structure and the identification of hepatocyte syndecan-1 as the primary proteoglycan that mediates triglyceride-rich lipoprotein clearance.
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PMID:Hepatic heparan sulfate proteoglycans and endocytic clearance of triglyceride-rich lipoproteins. 2080 47

The ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family consists of 19 proteases. These enzymes are known to play important roles in development, angiogenesis and coagulation; dysregulation and mutation of these enzymes have been implicated in many disease processes, such as inflammation, cancer, arthritis and atherosclerosis. This review briefly summarizes the structural organization and functional roles of ADAMTSs in normal and pathological conditions, focusing on members that are known to be involved in the degradation of extracellular matrix and loss of cartilage in arthritis, including the aggrecanases (ADAMTS-4 and ADAMTS-5), ADAMTS-7 and ADAMTS-12, the latter two are associated with cartilage oligomeric matrix protein (COMP), a component of the cartilage extracellular matrix (ECM). We will discuss the expression pattern and the regulation of these metalloproteinases at multiple levels, including their interaction with substrates, induction by pro-inflammatory cytokines, protein processing, inhibition (e.g., TIMP-3, alpha-2-macroglobulin, GEP), and activation (e.g., syndecan-4, PACE-4).
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PMID:The role of ADAMTSs in arthritis. 2120 96


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