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)

The effect of incubation on the content of endogenous intact plasma lipoprotein (LP) has been examined in minced samples of normal intima and lesions from 38 patients. Both the electrophoretically mobile and the immobilized LP fractions decreased on incubation, and the rate of destruction was proportional to LP concentration (r=0.832, p less than 0.001). Mincing the intima with EDTA before incubation increased the rate of destruction about 4-fold in fibrous lesions but not in lesions containing numerous fat-filled cells. The destruction of LP was highly dependent on pH; the rate was highest below pH 5.5 and destruction was almost completely inhibited above pH 6.4. In standard cathepsin assays haemoglobin substrate was hydrolysed at a rate comparable to the rate of destruction of LP. The results suggest that LP may be degraded by a lysosomal cathepsin in intima.
Atherosclerosis 1977 Apr
PMID:Destruction of endogenous low density lipoprotein in incubated intima. 1 24

Some important enzymes concerned with the biosynthesis of the precursors of glycosaminoglycans (gg), degradation of gg and biological sulphation have been studied in rats fed an atherogenic diet. L-Glutamine-D-fructose-6-phosphate amino-transferase and glucosamine-6-phosphate-N-acetylase--2 enzymes concerned with the biosynthesis of hexosamine precursors of gg--decreased in the liver in rats fed the atherogenic diet. UDPG pyrophosphorylase, UDPG dehydrogenase and UDPG glucuronic acid-5'-epimerase, which are concerned with the biosynthesis of the uronic precursors of gg, also decreased in the liver in the diet-fed rats. The activities of some of the enzymes concerned with degradation of gg-hyaluronidase, beta-glucuronidase beta-hexosaminidase, cathepsin and aryl sulphatase--increased both in the liver and aorta. The hepatic concentration of PAPS significantly decreased in the diet-fed rats. The sulphate-activating system, which includes ATP sulphurylase, APS kinase and sulphotransferase, also decreased. Thus the overall picture is one of decreased synthesis of gg and their increased degradation in the atheromatous rats.
Atherosclerosis
PMID:Metabolism of glycosaminoglycans in atheromatous rats. Enzymes concerned with synthesis, degradation and sulphation of glycosaminoglycans. 12 76

Prolonged exposure of rats to cigarette smoke resulted in significant alteration in the metabolism of glycosaminoglycans (GAG) and glycoproteins (GP). The concentration of many GAG fractions generally decreased in the aorta, liver and heart, but increased in the lungs. Concentration of chondroitin sulphates decreased in all the tissues. The activity of many enzymes concerned with the degradation of GAG (hyaluronidase, beta-glucuronidase and cathepsin-D) showed increase in these tissues. The concentration of the carbohydrate components (total hexose fucose and sialic acid) of aorta, heart and liver showed decrease in the rats exposed to cigarette smoke while there was increase in the lungs. The activity of many glycohydrolases generally showed increase in these tissues. Thus, exposure of rats to cigarette smoke for long periods produced changes in the aortic GAG and GP which are similar to those observed in atherosclerosis. On the other hand there was accumulation of many GAG in the lung tissue.
Atherosclerosis 1991 Jan
PMID:Changes in the glycosaminoglycans and glycoproteins in the tissues in rats exposed to cigarette smoke. 206 35

Cathepsin S is a cysteine protease with potent endoproteolytic activity and a broad pH profile. Cathepsin S activity is essential for complete processing of the MHC class II-associated invariant chain within B cells and dendritic cells, and may also be important in extracellular matrix degradation in atherosclerosis and emphysema. Unique among cysteine proteases, cathepsin S activity is up-regulated by IFN-gamma. Given its importance, we sought to elucidate the pathway by which IFN-gamma increases cathepsin S expression. Our data demonstrate that the cathepsin S promoter contains an IFN-stimulated response element (ISRE) that is critical for IFN-gamma-induced gene transcription in a cell line derived from type II alveolar epithelial (A549) cells. IFN response factor (IRF)-2 derived from A549 nuclear extracts associates with the ISRE oligonucleotide in gel shift assays, but is quickly replaced by IRF-1 following stimulation with IFN-gamma. The time course of IRF-1/ISRE complex formation correlates with increased levels of IRF-1 protein and cathepsin S mRNA. Overexpression of IRF-1, but not IRF-2, markedly augments cathepsin S promoter activity in A549 cells. Furthermore, overexpression of IRF-1 increases endogenous cathepsin S mRNA levels in 293T epithelial cells. Finally, freshly isolated bone marrow cells from IRF-1(-/-) mice fail to up-regulate cathepsin S activity in response to IFN-gamma. Thus, IRF-1 is the critical transcriptional mediator of IFN-gamma-dependent cathepsin S activation. These data elucidate a new pathway by which IRF-1 may affect MHC class II processing and presentation.
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PMID:IFN regulatory factor-1 regulates IFN-gamma-dependent cathepsin S expression. 1197 Sep 93

Several groups of proteolytic enzymes are able to degrade components of the extracellular matrix. During atherosclerosis, matrix remodeling is believed to influence the migration and proliferation of cells within the plaque. In the present study, gene expression of several proteases and their inhibitors was analyzed during the development of atherosclerosis in apolipoprotein E-deficient (ApoE-/-) mice. Quantitative real-time polymerase chain reaction was used to study gene expression of proteases after 10 and 20 weeks in ApoE-/- and C57BL/6 mice and in atherosclerotic lesions and nonaffected regions of the same ApoE-/- mouse. Some of the differentially expressed proteolytic enzymes were studied by immunohistochemistry. The matrix metalloproteinase (MMP)-9 and its inhibitor TIMP-1 were differentially expressed and the expression increased with time. Urokinase-type plasminogen activator showed no major expression. In contrast, cathepsins B, D, L, and S all showed strong and increased expression in ApoE-/- mice compared to C57BL/6 mice whereas the expression of their inhibitor, cystatin C, did not differ between the two mouse strains. The expression of cathepsins was mainly localized to the lesions and not to nonaffected regions of the aorta of ApoE-/- mice. Furthermore, cathepsin expression was similar to the expression of the macrophage marker macrosialin (CD68) although expression of cathepsins B, D, and L could be demonstrated in healthy C57BL/6 mice and in nonaffected vessel segments of atherosclerotic ApoE-/- mice. Cathepsin S mRNA expression was restricted to lesions of ApoE-/- mice. Furthermore, cathepsin S was the only cathepsin that was expressed in the media and absent in lipid-rich regions. All cathepsins studied showed intimal expression, the degree and localization of which differed between individual cathepsins. In conclusion, increased expression of several cathepsins in atherosclerotic lesions suggests that these proteases may participate in the remodeling of extracellular matrix associated with the atherosclerotic process.
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PMID:Differential expression of cysteine and aspartic proteases during progression of atherosclerosis in apolipoprotein E-deficient mice. 1221 22

In atherosclerosis, accumulation of cholesterol in macrophages may partially depend on its defective removal by high-density lipoproteins (HDL). We studied the proteolytic effect of cathepsins F, S, and K on HDL(3) and on lipid-free apoA-I, and its consequence on their function as inductors of cholesterol efflux from cholesterol-filled mouse peritoneal macrophages in vitro. Incubation of HDL(3) with cathepsin F or S, but not with cathepsin K, led to rapid loss of prebeta-HDL, and reduced cholesterol efflux by 50% in only 1min. Cathepsins F or K partially degraded lipid-free apoA-I and reduced its ability to induce cholesterol efflux, whereas cathepsin S totally degraded apoA-I, leading to complete loss of apoA-I cholesterol acceptor function. These results suggest that cathepsin-secreting cells induce rapid depletion of lipid-poor (prebeta-HDL) and lipid-free apoA-I and inhibit cellular cholesterol efflux, so tending to promote the formation and maintenance of foam cells in atherosclerotic lesions.
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PMID:Cathepsins F and S block HDL3-induced cholesterol efflux from macrophage foam cells. 1465 73

Atherosclerosis is an inflammatory disease characterized by extensive remodeling of the extracellular matrix architecture of the arterial wall. Although matrix metalloproteinases and serine proteases participate in these pathologic events, recent data from atherosclerotic patients and animals suggest the participation of lysosomal cysteine proteases in atherogenesis. Atherosclerotic lesions in humans overexpress the elastolytic and collagenolytic cathepsins S, K, and L but show relatively reduced expression of cystatin C, their endogenous inhibitor, suggesting a shift in the balance between cysteine proteases and their inhibitor that favors remodeling of the vascular wall. Extracts of human atheromatous tissue show greater elastolytic activity in vitro than do those from healthy donors. The cysteinyl protease inhibitor E64d limits this increased elastolysis, indicating involvement of cysteine proteases in elastin degradation during atherogenesis. Furthermore, inflammatory cytokines augment expression and secretion of active cysteine proteases from cultured monocyte-derived macrophages, vascular smooth muscle cells, and endothelial cells and increase degradation of extracellular elastin and collagen. Cathepsin S-deficient cells or those treated with E64d show significantly impaired elastolytic or collagenolytic activity. Additionally, recent in vivo studies of atherosclerosis-prone, LDL receptor-null mice lacking cathepsin S show participation of this enzyme in the initial infiltration of leukocytes, medial elastic lamina degradation, endothelial cell invasion, and neovascularization, illustrating an important role for cysteine proteases in arterial remodeling and atherogenesis.
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PMID:Lysosomal cysteine proteases in atherosclerosis. 1517 58

Atherosclerosis is characterized by a thickening and loss of elasticity of the arterial wall. Loss of elasticity has been attributed to the degradation of the arterial elastin matrix. Cathepsins K and S are papain-like cysteine proteases with known elastolytic activities, and both enzymes have been identified in macrophages present in plaque areas of diseased blood vessels. Here we demonstrate that macrophages express a third elastolytic cysteine protease, cathepsin V, which exhibits the most potent elastase activity yet described among human proteases and that cathepsin V is present in atherosclerotic plaque specimens. Approximately 60% of the total elastolytic activity of macrophages can be attributed to cysteine proteases with cathepsins V, K, and S contributing equally. From this 60%, two-thirds occur extracellularly and one-third intracellularly with the latter credited to cathepsin V. Ubiquitously expressed glycosaminoglycans (GAGs) such as chondroitin sulfate specifically inhibit the elastolytic activities of cathepsins V and K via the formation of specific cathepsin-GAG complexes. In contrast, cathepsin S, which does not form complexes with chondroitin sulfate is not inhibited; thus suggesting a specific regulation of elastolytic activities of cathepsins by GAGs. Because the GAG content is reduced in atherosclerotic plaques, an increase of cathepsins V and K activities may accelerate the destruction of the elastin matrix in diseased arteries.
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PMID:Cathepsin V, a novel and potent elastolytic activity expressed in activated macrophages. 1519 1

Cathepsin S is a cysteine protease in the papain super-family. Studies have shown that it is highly expressed in antigen-presenting cells. Along with other lysosomal proteases, cathepsin S plays an important role in the major histocompatibility complex class II-restricted antigen presentation, especially in the degradation of the invariant chain, a chaperone peptide bound to the class II complex. Compared with other lysosomal cysteine proteases, cathepsin S has displayed some unique characteristics. As a result, cathepsin S has been implicated as a potential target in the treatment of various disorders ranging from autoimmune diseases to atherosclerosis. Furthermore, a number of small-molecule cathepsin S inhibitors have demonstrated efficacy in disease-relevant models.
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PMID:Cysteine protease cathepsin S as a key step in antigen presentation. 1533 87

Matrix remodelling plays an important role in regulating plaque stability. Cystatin C, an inhibitor of the elastin-degrading cysteine proteases of the cathepsin family, is believed to be one of the key protease inhibitors in this process. The aim of the present study was to investigate the role of leukocyte-specific cystatin C expression under conditions that favour plaque regression. Apolipoprotein E-deficient mice (apoE-/-) were given a Western-type diet 15 weeks prior transplantation with bone marrow from mice lacking cystatin C (cysC-/-) or cystatin C positive (cysC+/+) mice, in both cases apoE+/+ to create conditions favouring plaque regression. Transplantations were verified with PCR and Western analyses. Transplanted mice showed a 70% decrease in lipid content and reduction in plaque area compared to baseline ApoE-/- mice, demonstrating plaque regression due to apoE expression in macrophages. apoE-/- mice transplanted with cysC-/- bone marrow were then compared to mice transplanted with cysC+/+ bone marrow. Mice receiving cysC-/- bone marrow had a 30% larger plaque area, despite absence of significant differences in plasma cholesterol and lipid contents in plaque. Unexpectedly, mice transplanted with cystatin C-deficient bone marrow cells had increased elastin and collagen content in lesions. These observations suggest that leukocyte-specific expression of cystatin C is actively involved in matrix remodelling associated with plaque regression.
Atherosclerosis 2005 May
PMID:Absence of the protease inhibitor cystatin C in inflammatory cells results in larger plaque area in plaque regression of apoE-deficient mice. 1582 74


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