Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Members of the family of large chondroitin sulfate proteoglycans (CSPGs), such as versican and aggrecan, are involved in early heart development, and in the development and progression of atherosclerosis and restenosis. Given the important roles played by versican and aggrecan in such processes, we sought to determine whether these molecules are present in the aortic wall during the advanced stages of chicken embryo development and the endothelial-mesenchymal transformation (EMT). Immunolabeling of serial cryosections revealed versican immunoreactivity around the cells within the intimal thickening, and the cells organized in lamellar and interlamellar cell layers. In contrast, a weak aggrecan immunoreactivity was limited to the cells arranged into lamellar and interlamellar cell layers. Immunolabeling also demonstrated that V2 is the main versican isoform present at the intimal thickening. According to immunoblotting analysis, the aggrecan content was very low in all stages examined, and two versican isoforms (V0 and V2) were present at day 14 of development. We also investigated whether versican isoforms were present during EMT in vitro. Versican immunoreactivity was detected in patches of endothelial cells; in the detaching and migrating cells, and the extracellular matrix (ECM) deposited by them; and in cells that had acquired mesenchymal characteristics. These data indicate that versican and aggrecan have different spatial and temporal patterns of expression, and they have different functions during remodeling of the aortic wall. Also, the different immunoreactivity and immunolocalization patterns observed for versican both in vivo and in vitro, in addition to being associated with the presence of different versican isoforms, may be related to the predominance of the V2 isoform during intimal thickening formation and EMT.
 ...
PMID:Differential versican isoforms and aggrecan expression in the chicken embryo aorta. 1522 1

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.
 ...
PMID:Induction of synthesis of a large heparan sulfate proteoglycan, perlecan, by thrombin in cultured human coronary smooth muscle cells. 1571 25

The propensity to develop atherosclerosis varies markedly among different sites in the human vasculature. To determine a possible cause for such differences in atherosclerosis susceptibility, a proteomics-based approach was used to assess the extracellular proteoglycan core protein composition of intimal hyperplasia from both the atherosclerosis-prone internal carotid artery and the atherosclerosis-resistant internal thoracic artery. The intimal proteoglycan composition in these preatherosclerotic lesions was found to be more complex than previously appreciated with up to eight distinct core proteins present, including the large extracellular proteoglycans versican and aggrecan, the basement membrane proteoglycan perlecan, the class I small leucine-rich proteoglycans biglycan and decorin, and the class II small leucine-rich proteoglycans lumican, fibromodulin, and prolargin/PRELP (proline arginine-rich end leucine-rich repeat protein). Although most of these proteoglycans seem to be present in similar amounts at the two locations, there was a selective enhanced deposition of lumican in the intima of the atherosclerosis-prone internal carotid artery compared with the intima of the atherosclerosis-resistant internal thoracic artery. The enhanced deposition of lumican in the intima of an atherosclerosis prone artery has important implications for the pathogenesis of atherosclerosis.
 ...
PMID:Analysis of intimal proteoglycans in atherosclerosis-prone and atherosclerosis-resistant human arteries by mass spectrometry. 1597 May 83

The exchangeable apolipoproteins present in small, dense LDL (sdLDL) and large, buoyant LDL subclasses were evaluated with a quantitative proteomic approach in patients with the metabolic syndrome and with type 2 diabetes, both with subclinical atherosclerosis and the B LDL phenotype. The analyses included surface-enhanced laser adsorption/ionization, time-of-flight mass spectrometry, and subsequent identification by mass spectrometry or immunoblotting and were carried out in LDL subclasses isolated by ultracentrifugation in deuterium oxide gradients with near physiological salt concentrations. The sdLDLs of both types of patients were enriched in apolipoprotein C-III (apoC-III) and were depleted of apoC-I, apoA-I, and apoE compared with matched healthy controls with the A phenotype. The LDL complexes formed in serum from patients with diabetes with the arterial proteoglycan (PG) versican were also enriched in apoC-III. In addition, there was a significant correlation between the apoC-III content in sdLDL in patients and the apparent affinity of their LDLs for arterial versican. The unique distribution of exchangeable apolipoproteins in the sdLDLs of the patients studied, especially high apoC-III, coupled with the augmented affinity with arterial PGs, may contribute to the strong association of the dyslipidemia of insulin resistance with increased risk for cardiovascular disease.
 ...
PMID:A proteomic study of the apolipoproteins in LDL subclasses in patients with the metabolic syndrome and type 2 diabetes. 1599 72

We have detected versican, a member of the large chondroitin sulfate proteoglycans, and its degraded C-terminal G3 fragments in human plasma and observed that the versican G3 domain promoted blood coagulation. Silencing G3 expression with small interfering RNA reduced the effect of G3 on coagulation. Plasma coagulation assays suggest that G3 enhances coagulation irrespective of its actions on platelets and white blood cells. To examine how versican affected blood coagulation, we used normal human plasma and different types of coagulation factor-deficient plasmas. The experiments indicated that versican enhanced coagulation through the extrinsic pathway, and that Factor VII was the target molecule. FVII activity assays showed that G3 activated FVII in the presence of plasma but not with purified FVII directly. Yeast two-hybrid, immunoprecipitation, and gel co-migration assays showed that G3 interacted with the tissue factor pathway inhibitor-1 (TFPI-1). TFPI-1 activity assays suggested that G3 inhibited TFPI-1 activity, allowing FVIIa and FXa to facilitate the coagulation process. G3-induced blood coagulation was further confirmed with a mouse model in a real-time manner. Taken together, these results indicate that versican may represent a new target for the development of therapies against atherosclerosis.
 ...
PMID:Versican G3 domain promotes blood coagulation through suppressing the activity of tissue factor pathway inhibitor-1. 1643 24

Heparan sulfate in the extracellular matrix of the artery wall has been proposed to possess anti-atherogenic properties by interfering with lipoprotein retention, suppression of inflammation, and inhibition of smooth muscle cell growth. Previously, the amount of heparan sulfate in atherosclerotic lesions from humans and animals has been shown to be reduced but the identity or identities of the heparan sulfate molecules being down regulated in this disease are not known. In this study, atherosclerotic lesions were retrieved from 44 patients undergoing surgery for symptomatic carotid stenosis. Normal iliac arteries from organ donors were used as controls. Analysis of the specimens by gene microarray showed a selective reduction in perlecan gene expression, whereas, expression of the other heparan sulfate proteoglycans in the artery wall, agrin and collagen XVIII, remained unchanged. Expression of the large chondroitin sulfate proteoglycan, versican, also remained unchanged. Real-time PCR confirmed the decrease in perlecan gene expression and the unchanged expression of versican. The findings were supported by immunohistochemical analysis demonstrating a reduced accumulation of both perlecan core protein and heparan sulfate in carotid lesions. The study demonstrates a reduction of perlecan mRNA-expression and protein deposition in human atherosclerosis, which in part explains the low levels of heparan sulfate in this disease.
Atherosclerosis 2007 Feb
PMID:Reduced perlecan expression and accumulation in human carotid atherosclerotic lesions. 1662 Aug 36

ADAMTS1 is an extracellular metalloproteinase known to participate in a variety of biological processes that includes inflammation, angiogenesis, and development of the urogenital system. Many of its functions rely on its catalytic activity, which thus far has been limited to the cleavage of the matrix proteoglycans aggrecan and versican. However, it is likely that other substrates exist. Using a yeast two-hybrid screen, we identified the Kunitz-type inhibitor, tissue factor pathway inhibitor-2 (TFPI-2), as a binding partner of ADAMTS1. The interaction was confirmed by several biochemical and cell-based assays. In addition, our studies revealed alterations in the pattern of TFPI-2-secreted isoforms and in its extracellular location caused by the specific action of ADAMTS1. Interestingly, we found that TFPI-2 is a novel substrate of ADAMTS1. The cleavage removes a protease-sensitive C-terminal region in TFPI-2, altering its binding properties. The proposed role of TFPI-2 as a maintenance factor of extracellular remodeling suggests the indirect function of ADAMTS1 as an additional homeostatic player by its ability to alter the extracellular location of TFPI-2 and, therefore, to disrupt the remodeling machinery, a phenomenon directly associated to pathologies such as atherosclerosis and tumor progression.
 ...
PMID:ADAMTS1 interacts with, cleaves, and modifies the extracellular location of the matrix inhibitor tissue factor pathway inhibitor-2. 1664 Oct 89

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.
 ...
PMID:Interleukin-1beta selectively decreases the synthesis of versican by arterial smooth muscle cells. 1722 75

Patients with diabetes are at substantially increased risk for atherosclerosis and clinical cardiovascular events. Because arterial extracellular matrix contains several molecules, including biglycan, versican, hyaluronan, and elastin, that may affect plaque lipid retention and stability, we determined whether diabetes affects plaque content of these molecules in a porcine model of hyperlipidemia and diabetes. Coronary artery sections were studied from non-diabetic normolipidemic (n=11, N-NL), diabetic normolipidemic (n=10, DM-NL), non-diabetic hyperlipidemic (n=16, N-HL), and diabetic hyperlipidemic (n=15, DM-HL) animals. Hyaluronan, biglycan, versican, and apolipoprotein B (apoB) were detected with monospecific peptides or antisera, and elastin with Movat's pentachrome stain, and contents of each were quantified by computer-assisted morphometry. In the hyperlipidemic groups, diabetes was associated with a 4-fold increase in intimal area, with strong correlations between intimal area and immunostained areas for hyaluronan (R(2) = 0.83, p<0.0001), biglycan (R(2) = 0.72, p<0.0001), and apoB (R(2) = 0.23, p=0.0069). In contrast, median (interquartile range) intimal elastin content was significantly lower with diabetes [N-HL: 5.2% (2.4-8.2%) vs DM-HL: 1.5% (0.5-4.2%), p=0.01], and there was a strong negative correlation between intimal total and elastin areas (Spearman r = -0.62, p=0.001). In this porcine model, diabetes was associated with multiple extracellular matrix changes that have been associated with increased lesion instability, greater atherogenic lipoprotein retention, and accelerated atherogenesis.
 ...
PMID:Diabetes and arterial extracellular matrix changes in a porcine model of atherosclerosis. 1765 66

Monocyte adhesion to endothelium plays an important role in atherosclerosis. We investigated the effects of micronutrients on monocyte-binding properties of extracellular matrix (ECM) produced by human aortic endothelial cells (AoEC). Confluent cultures of AoEC were exposed to ascorbic acid, quercetin, gotu kola extract (10% asiatic acid), green tea extract (40% epigallocatechin gallate), or a mixture of these micronutrients for 48 hours. AoEC-produced ECM was exposed by differential treatment. U937 monocyte adhesion was assayed by fluorescence. ECM composition was assayed immunochemically and with radiolabeled metabolic precursors. AoEC exposure to micronutrients reduced ECM capacity to bind monocytes in a dose-dependent manner. This effect was accompanied by profound changes in the ECM composition. Correlation analysis revealed that changes in monocyte adhesion to ECM had the strongest positive correlation with ECM content for laminin (CC = 0.9681, P < 0.01), followed by fibronectin, collagens type III, I, and IV, biglycan, heparan sulfate, and elastin. The strongest negative correlation was with chondroitin sulfate (CC = -0.9623, P < 0.01), followed by perlecan and versican. Individual micronutrients had diverse effects on ECM composition and binding properties, and their mixture was the most effective treatment. In conclusion, micronutrient-dependent reduction of monocyte adhesion to endothelium is partly mediated through specific modulation of ECM composition and properties.
 ...
PMID:Plant-derived micronutrients suppress monocyte adhesion to cultured human aortic endothelial cell layer by modulating its extracellular matrix composition. 1859 73


<< Previous 1 2 3 4 Next >>