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)

Human leucocyte elastase is a serine proteinase involved in phagocytosis, defence against invading micro-organisms, degradation of elastin, collagen, proteoglycans, fibrinogen and fibrin, being also responsible for the digestion of damaged tissues and of the bacterial degradation products. Lack of the enzyme regulation is at the basis of pathological states, such as pulmonary emphysema, cystic fibrosis, rheumatoid arthritis, atherosclerosis and glomerulonephritis. A detailed characterisation of the enzyme:inhibitor recognition process, based on extensive thermodynamic, kinetic and structural information, as well as on the comparative analysis with the homologous proteinase from porcine pancreas, is reported in the present review.
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PMID:Molecular bases for human leucocyte elastase inhibition. 804 99

Individuals with hepatic lipase (HL) deficiency are often characterized by elevated levels of triglycerides and cholesterol and may be subject to premature atherosclerosis. Missense mutations in the HL gene have been identified in two affected families: substitutions of serine for phenylalanine at amino acid 267 and threonine for methionine at amino acid 383 (S267F and T383M, respectively). To confirm the role of S267F and T383M, respectively). To confirm the role of mutations separately into human HL cDNA by site-directed mutagenesis, and the resulting constructs were independently expressed in COS cells. HL activity and mass were measured and compared with wild-type HL transfectants to determine the effect of these mutations on lipase activity and secretion. Although similar amounts of HL protein were detected intracellularly after transfection with the wild-type and mutant constructs, S267F and T383M HL activity levels were markedly decreased: in S267F, no HL activity was detected, and activity levels in T383M were 38% of wild-type HL. Heparin-induced secretion of the two HL mutants was also severely affected: no detectable activity could be measured in the media of S267F, although some inactive mass (12% of wild-type HL) was secreted; mutant T383M secreted 4% and 20% of wild-type activity and mass, respectively. These results indicate that the single amino acid substitution present in HL S267F is sufficient to render the enzyme completely nonfunctional; in contrast, the T383M mutant retains partial activity but is poorly secreted. Thus, these defects appear capable of accounting for the HL-deficient phenotypes exhibited by individuals carrying the T383M and S267F mutations.
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PMID:Molecular characterization of human hepatic lipase deficiency. In vitro expression of two naturally occurring mutations. 812 42

To contribute to the analysis of the genetic background of atherosclerosis, especially endothelial dysfunction, we searched for DNA polymorphisms in the genes encoding E-, P-, and L-selectin, and ICAM-I and VCAM-I. We detected 17 mutations by single-strand conformation polymorphisms analysis and direct sequencing. Five of them resulted in an amino acid substitution. In E-selectin, exchanges from serine to arginine (position 128), from leucine to phenylalanine (position 554), and a DNA mutation from guanine to thymine (position 98) present significantly different allele frequencies in young patients with angiographically established, severe atherosclerosis, compared with an unselected population. Results suggest that these polymorphisms are associated with a higher risk for early severe atherosclerosis.
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PMID:DNA polymorphisms in adhesion molecule genes--a new risk factor for early atherosclerosis. 855 54

Thrombin's proteolytically activated "tethered-ligand" receptor is widely expressed and mediates many of thrombin's actions on cells. Its central role in thrombin-stimulated human platelet activation and vascular smooth muscle proliferation as well as location in atherosclerotic plaques suggests receptor involvement in arterial thrombosis and atherosclerosis. Thrombin receptor antagonists, should they be effective, could be more selective than thrombin active site inhibitors in antithrombotic therapy as well as other indications. Blocking antibodies to peptides derived from the thrombin receptor have been used as prototypical thrombin receptor antagonists in vitro and have been useful in implicating this receptor in thrombin's actions on a variety of cell types. These antibodies have also shown the involvement of the receptor in arterial thrombosis models in nonhuman primates. Amino acid substitution studies have shown the structural requirements for receptor activation of peptides homologous to the new NH2-terminus. Peptide-based partial agonists and antagonists have been synthesized by NH2-terminal replacements of the serine in the receptor activating peptides. Current thrombin receptor antagonists lack potency and some are partial agonists; however, it is expected that more potent compounds will result from further investigation. The potency limitations are important to overcome before serious evaluation of their efficacy can be determined.
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PMID:Thrombin receptor antagonists. 883 6

1. Transforming growth factors-beta (TGF-beta) are multifunctional proteins that regulate cell growth, differentiation, migration and extracellular matrix production and have an important role in embryonic development and tissue remodelling. 2. The diverse biological actions of TGF-beta are elicited following their interaction with type I and type II TGF-beta receptors, both of which are transmembrane serine/threonine kinases, suggesting an important role for protein phosphorylation in the mechanism of action of these cytokines on the growth of cells and their extracellular environment. 3. Alterations in TGF-beta gene expression and action in various cell types associated with the cardiovascular system may contribute to the pathophysiology of a number of diseases, such as hypertension, atherosclerosis and restenosis, as well as the development of cardiac abnormalities.
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PMID:Regulation and interactions of transforming growth factor-beta with cardiovascular cells: implications for development and disease. 893 7

In a group of unrelated Danish patients with familial hypercholesterolemia (FH) we recently reported two common low-density lipoprotein (LDL) receptor mutations, W23X and W66G, accounting for 30% of the cases. In this study, we describe another common LDL receptor mutation, a G to C transition at cDNA position 1730 in exon 12, causing a tryptophan to serine substitution in amino acid position 556 (W556S). In the Danish patients, the W556S mutation was present in 12% of 65 possible mutant alleles. The pathogenicity of the W556S mutation, which is located in one of the five conserved motifs Tyr-Trp-Thr-Asp in the epidermal growth factor homology region, was studied in transfected COS-7 cells expressing normal and mutant LDL receptor cDNAs. Results obtained by immunofluorescence flow cytometry and confocal microscopy, as well as by immunoprecipitation, were compatible with complete retention of the mutant protein in the endoplasmic reticulum. The transport-defective W556S mutation and the W23X and W66G mutations seem to account for about 40% of the LDL receptor defects in Danish families with FH.
Atherosclerosis 1997 May
PMID:A common W556S mutation in the LDL receptor gene of Danish patients with familial hypercholesterolemia encodes a transport-defective protein. 918 Feb 46

Angiotensin (Ang) II plays an important role in cardiovascular homeostasis such as regulation of blood pressure and tissue remodeling. Alternative Ang II-forming pathways, independent of Ang I converting enzyme (ACE), have been reported. Several serine proteinases including kallikrein, cathepsin G and chymase appear to be involved in ACE-independent Ang II formation in vivo. Among them, biochemical analysis revealed that chymase is a highly efficient Ang II-forming enzyme with a high substrate specificity against Ang I and is rich in various human tissues. However, the pathophysiological roles of chymase have not yet been clarified. Recent reports from us and others indicated that chymase seems to be related to development of atherosclerosis, cardiomyopathy, remodeling of cardiovascular tissues, rheumatoid arthritis and etc. In this review article, the recent findings for chymase related to cardiovascular diseases are summarized.
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PMID:[Pathophysiological roles of human chymase]. 928

Epidemiological studies have provided strong evidence that an elevated plasma homocysteine concentration is an important independent risk factor for cardiovascular disease. We have shown, in the rat, that the kidney is a major site for the removal and subsequent metabolism of plasma homocysteine [Bostom, Brosnan, Hall, Nadeau and Selhub (1995) Atherosclerosis 116, 59-62]. To characterize the role of the kidney in homocysteine metabolism further, we measured the disappearance of homocysteine in isolated renal cortical tubules of the rat. Renal tubules metabolized homocysteine primarily through the transulphuration pathway, producing cystathionine and cysteine (78% of homocysteine disappearance). Methionine production accounted for less than 2% of the disappearance of homocysteine. Cystathionine, and subsequently cysteine, production rates, as well as the rate of disappearance of homocysteine, were sensitive to the level of serine in the incubation medium, as increased serine concentrations permitted higher rates of cystathionine and cysteine production. On the basis of enrichment profiles of cystathionine beta-synthase and cystathionine gamma-lyase, in comparison with marker enzymes of known location, we concluded that cystathionine beta-synthase was enriched in the outer cortex, specifically in cells of the proximal convoluted tubule. Cystathionine gamma-lyase exhibited higher enrichment patterns in the inner cortex and outer medulla, with strong evidence of an enrichment in cells of the proximal straight tubule. These studies indicate that factors that influence the transulphuration of homocysteine may influence the renal clearance of this amino acid.
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PMID:Characterization of homocysteine metabolism in the rat kidney. 935 66

The subfraction of low density lipoprotein (LDL) with low sialic acid content that caused accumulation of cholesterol esters in human aortic smooth muscle cells has been found in the blood of coronary atherosclerosis patients. It was demonstrated that this subfraction consists of LDL with small size, high electronegative charge, reduced lipid content, altered tertiary structure of apolipoprotein B, etc. LDL of this subfraction is naturally occurring multiple-modified LDL (nomLDL). In this study we compared the binding, uptake and proteolytic degradation of native LDL and nomLDL by smooth muscle cells cultured from human grossly normal intima, fatty streaks, and atherosclerotic plaques. Uptake of nomLDL by normal and atherosclerotic cells was 3.5- and 6-fold, respectively, higher than uptake of native LDL. Increased uptake of nomLDL was due to increased binding of this LDL by intimal smooth muscle cells. The enhanced binding is explained by the interaction of nomLDL with cellular receptors other than LDL-receptor. Modified LDL interacted with the scavenger receptor, asialoglycoprotein receptor, and also with cell surface proteoglycans. Rates of degradation of nomLDL were 1.5- and 5-fold lower than degradation of native LDL by normal and atherosclerotic cells, respectively. A low rate of nomLDL degradation was also demonstrated in homogenates of intimal cells. Activities of lysosomal proteinases of atherosclerotic cells were decreased compared with normal cells. Pepstatin A, a cathepsin D inhibitor, completely inhibited lipoprotein degradation, while serine, thiol, or metallo-proteinase inhibitors had partial effect. This fact reveals that cathepsin D is involved in initial stages of apoB degradation by intimal smooth muscle cells. Obtained data show that increased uptake and decreased lysosomal degradation of nomLDL may be the main cause of LDL accumulation in human aortic smooth muscle cells, leading to foam cell formation.
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PMID:Metabolism of native and naturally occurring multiple modified low density lipoprotein in smooth muscle cells of human aortic intima. 943 79

Hyperhomocysteinemia has been recognized as one of the risk factors for atherosclerosis and premature vascular disease. Patients on dialysis and end-stage renal disease also manifest high plasma concentrations of homocysteine. We performed this study to evaluate the effects of folic acid supplementation on hyperhomocysteinemia in CAPD patients. Twenty-three CAPD patients (8 males, 15 females, 49.1 +/- 14.2-years-old) dialyzed for 22.7 +/- 19.2 months participated in the study. Daily 5-mg doses of folic acid supplementation for 4 weeks significantly reduced plasma concentrations of total homocysteine (p < 0.01) and serine (p < 0.001). This observation suggests that the reduction of plasma concentrations of total homocysteine results from activation of homocysteine remethylation to methionine. On the other hand, folic acid supplementation also revealed significant correlations between changes in serum concentrations of both dihomo-gamma-linolenic acid and arachidonic acid and changes in plasma concentrations of total homocysteine (r = -0.517, p < 0.05, r = -0.451, p < 0.05, respectively). In addition, serum concentrations of both dihomo-gamma-linolenic acid and arachidonic acid in 11 CAPD patients with hyperhomocysteinemia (> or = 35 micromol/litter) were significantly lower than those of 12 CAPD patients with normohomocysteinemia (< 35 micromol/litter) (p < 0.05, p < 0.05, respectively). Serum concentrations of both dihomo-gamma-linolenic acid and arachidonic acid in CAPD patients with hyperhomocysteinemia increased significantly (p < 0.01, p < 0.05, respectively) and reached similar levels of CAPD patients with normohomocysteinemia, while plasma concentrations of total homocysteine decreased after folic acid supplementation. These findings suggest that correction of hyperhomocysteinemia in patients on dialysis produces an increase in unsaturated fatty acids.
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PMID:[Effects of folic acid supplementation on hyperhomocysteinemia in CAPD patients: effects on unsaturated fatty acids]. 951 77


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