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)

Though calcium plays an important role in a number of biologic processes related to the pathogenesis of atherosclerosis, the relationship of serum calcium and phosphorus levels with the angiographic severity of coronary artery disease (CAD) is not known. We retrospectively studied 376 stable patients (age range 31-86 years, mean 59.2 +/- 10.5 years; 68% males) undergoing routine coronary angiography and related the angiographic severity of CAD with the serum levels of total and corrected calcium, phosphorus, albumin, total protein and bicarbonate. The primary variable studied was the number of vessels with haemodynamically significant disease. On univariate analysis, total serum calcium and serum albumin levels had a negative association with the number of vessels diseased (P = 0.046 and 0.057, respectively). Multiple regression analysis using age, sex, smoking, diabetes, hypertension, hyperlipidaemia, ethnicity and family history, in addition to serum calcium, phosphorus and albumin levels as the predictor variables, showed that serum albumin has an independent negative and serum phosphorus has an independent positive association with the angiographic severity of CAD (P = 0.04 and 0.003, respectively; n = 294). Serum phosphorus level also showed highly significant positive associations with the presence of total or subtotal occlusion and with most severe stenosis observed on angiography. A moderate change in the serum level of albumin or phosphorus confers a risk similar to that associated with smoking, as estimated by the odds ratios.
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PMID:Serum calcium, phosphorus and albumin levels in relation to the angiographic severity of coronary artery disease. 920 42

The uptake of oxidized low density lipoprotein (OxLDL) by macrophages is a key event implicated in the initiation and development of atherosclerotic lesions. Two macrophage surface receptors, CD36 (a class B scavenger receptor) and the macrophage scavenger receptor (a class A scavenger receptor), have been identified as the major receptors that bind and internalize OxLDL. Expression of CD36 in monocyte/macrophages in tissue culture is dependent both on the differentiation state as well as exposure to soluble mediators (cytokines and growth factors). The regulatory mechanisms of this receptor in vivo are undetermined as is the role of lipoproteins themselves in modulating CD36 expression. We studied the effect of lipoproteins, native LDL and modified LDL (acetylated LDL (AcLDL) and OxLDL) on the expression of CD36 in J774 cells, a murine macrophage cell line. Exposure to lipoproteins resulted in a marked induction of CD36 mRNA expression (4-8-fold). Time course studies showed that maximum induction was observed 2 h after treatment with AcLDL and at 4 h with LDL and OxLDL. Increased expression of CD36 mRNA persisted for 24 h with each treatment group. Induction of CD36 mRNA expression was paralleled by an increase in CD36 protein as determined by Western blot with the greatest induction by OxLDL (4-fold). In the presence of actinomycin D, treatment of macrophages with LDL, AcLDL, or OxLDL did not affect CD36 mRNA stability, implying that CD36 mRNA was transcriptionally regulated by lipoproteins. To determine the mechanism(s) by which lipoproteins increased expression of CD36 we evaluated the effects of lipoprotein components on CD36 mRNA expression. ApoB 100 increased CD36 mRNA expression significantly, whereas phospholipid/cholesterol liposomes had less effect. Incubation of macrophages with bovine serum albumin or HDL reduced expression of CD36 mRNA in a dose-dependent manner. Finally, to evaluate the in vivo relevance of the induction of CD36 mRNA expression by lipoproteins, peritoneal macrophages were isolated from mice following intraperitoneal injection of lipoproteins. Macrophage expression of CD36 mRNA was significantly increased by LDL, AcLDL, or OxLDL in relation to mice infused with phosphate-buffered saline, with OxLDL causing the greatest induction (8-fold). This is the first demonstration that exposure to free and esterified lipids augments functional expression of the class B scavenger receptor, CD36. These data imply that lipoproteins can further contribute to foam cell development in atherosclerosis by up-regulating a major OxLDL receptor.
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PMID:Native and modified low density lipoproteins increase the functional expression of the macrophage class B scavenger receptor, CD36. 926 Nov 89

Several studies showed a diminished production of the endothelium-derived relaxing factor nitric oxide (NO) in the early stage of atherosclerosis. The inhibition of NO-production seems to be mediated by lipoproteins, especially oxidized low-density lipoproteins (ox-LDL). There is some evidence, that the interactions of lipoproteins and NO are associated with the phospholipid fraction of lipoproteins. Since fatty acids have different atherogenic properties-depending on chain length, degree of saturation and steric configuration-, we investigated the effect of fatty acids on endothelial NO-production. Human umbilical vein endothelial cells were incubated with palmitic acid and stearic acid in different concentrations in culture medium enriched with serum albumin for five hours. After that, NO-production was stimulated by calcium-ionophore A23187. NO-production was determined by a bioassay method using RFL-6 cells followed by radioimmunological determination of cGMP. NO-production stimulated by calcium-ionophore A23187(100%) was decreased by palmitic acid (10, 50, 100 microM) to 79 +/- 12%; 63 +/- 10% and 53 +/- 14%. In contrast, incubation with stearic acid (10, 50 and 100 microM) had no effect on A23187-stimulated NO-production (94 +/- 11%; 93 +/- 11%; 104 +/- 15%). Thus, palmitic acid but not stearic acid dose-dependently inhibited NO-release by endothelial cells. These different actions parallel the differing atherogenic potential of the two fatty acids.
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PMID:Palmitic acid but not stearic acid inhibits NO-production in endothelial cells. 928 52

Human serum albumin minimally-modified by methylglyoxal (MGmin-HSA) stimulated the synthesis and secretion of tumour necrosis factor-alpha (TNF-alpha) from human monocytic THP-1 cells in vitro. Human serum albumin minimally-modified by glucose-derived advanced glycation endproducts (AGEmin-HSA) and human serum albumin highly-modified by glucose-derived advanced glycation endproducts (AGE-HSA) stimulated markedly lower synthesis and secretion of TNF-alpha from THP-1 cells than did MGmin-HSA. The median effective concentration EC50 value of MGmin-HSA for the secretion of TNF-alpha was 5.8 +/- 0.3 microM and the maximal secretion was 0.28 +/- 0.01 ng TNF-alpha/ml (n = 12) for incubations containing 5 x 10(5) cells/ml. MGmin-HSA (0.2-2.0 microM) also stimulated chemotaxis of THP-1 cells in vitro but AGE-HSA did not in this concentration range. The EC50 value of MGmin-HSA for the chemotactic response was 0.44 +/- 0.07 microM (n = 15). Similar induction of the synthesis and secretion of TNF-alpha and chemotaxis by monocytes in response to MGmin-HSA in vivo may contribute to atherosclerosis in macro- and micro-angiopathy, particularly in the development of chronic clinical complications of diabetes mellitus.
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PMID:Synthesis and secretion of tumour necrosis factor-alpha by human monocytic THP-1 cells and chemotaxis induced by human serum albumin derivatives modified with methylglyoxal and glucose-derived advanced glycation endproducts. 929 94

The effect of aminoguanidine (AG) on the expression of adhesion molecules on nonactivated human umbilical vein endothelial cells (HUVEC) was investigated in vitro. Nonactivated HUVEC cultivated on long-term glycated fibronectin (FN) as compared to native FN showed a significant upregulation of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1) and CD31 which could be further promoted by long-term glycated bovine serum albumin. AG, at a concentration of 0.01 mol/l, caused an upregulation of ICAM-1 of 48 +/- 17.4% in HUVEC cultivated on gelatin. In contrast, VCAM-1 and E-selectin remained unaffected. At this concentration, formation of advanced glycation end products (AGE) was inhibited by 57%, as determined immunologically, and by 50%, as verified by AGE-specific fluorescence. A hypothesis concerning the upregulation of ICAM-1 by AG as compared to VCAM-1 is proposed relating to its relative redox insensitivity. Our results demonstrate that the beneficial effect of AG in reducing the risk of accelerated development of atherosclerosis in diabetic patients by inhibiting formation of AGE on matrix proteins such as FN might be hampered by its tendency to upregulate ICAM-1 on endothelial cells.
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PMID:Effects of aminoguanidine on adhesion molecule expression of human endothelial cells. 934 1

Cardiovascular complications account for more than 50% of death in hemodialysis patients. Strong and independent predictors of mortality or cardiovascular complications are low levels of serum albumin, high plasma C-reactive protein and lipoprotein(a), plasma proteins that are described to function as negative or positive acute phase reactants. Further prominent and known risk factors that contribute to the increased incidence of atherosclerosis in hemodialysis patients are disorders in lipoprotein metabolism and elevated plasma fibrinogen concentrations. The latter has also been described to increase following acute or chronic inflammation. The main metabolic abnormality of the lipoprotein profile is a delayed catabolism of triglyceride-rich apoB-containing lipoproteins caused by a decreased activity of lipolytic enzymes. Inhibition of lipoprotein lipase activity by cytokines or parathyroid hormone impedes conversion of very-low-density lipoprotein to low-density lipoprotein, resulting in remnant accumulation and hypertriglyceridemia. Another acute phase condition, namely, acute myocardial infarction, results in a similar pattern of dyslipidemia and coagulation disorder. In summary, the acute phase response deeply influences serum lipids and lipoproteins as well as other atherogenic acute phase proteins in hemodialysis patients. Appreciation of acute phase lipoprotein changes is essential for accurate diagnosis of dyslipidemias, proper design of future clinical studies, and correct interpretation of published data.
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PMID:Inflammation, dyslipidemia and vascular risk factors in hemodialysis patients. 935 Jun 81

Free-radical oxidation of human plasma low-density lipoprotein (LDL) produces (carboxyalkyl)pyrrole (CAP) epitopes that were detected with enzyme-linked immunosorbent assays using antibodies raised against keyhole limpet hemocyanin (KLH)-bound 2-(omega-carboxyheptyl)-pyrrole (CHP) and 2-(omega-carboxypropyl)pyrrole (CPP). These antibodies exhibit high structural selectivity (< 0.5% cross-reactivity) in competitive binding inhibition assays with the corresponding human serum albumin (HSA)-bound pyrroles. No cross-reactivity was detected for HSA-bound 2-pentylpyrrole, an epitope that is generated by a reaction of 4-hydroxy-2-nonenal (HNE) with protein lysyl residues. Oxidation of either arachidonic or linoleic acid in the presence of HSA produced an HNE-derived 2-pentylpyrrole epitope. However, only oxidation of linoleic acid formed HSA-bound CHP, while only oxidation of arachidonic acid generated HSA-bound CPP. Since ester hydrolysis with KOH markedly elevated levels of immunoreactive epitopes detected in oxidized LDL, the CAPs are presumably generated by reactions of oxidized cholesteryl esters, triglycerides, and phospholipids with LDL protein, and only some of these oxidized esters are hydrolyzed, e.g., by phospholipase activity associated with LDL. Protein-bound CHP immunoreactivity was detected in human plasma, and levels are significantly elevated in renal failure and atherosclerosis patients compared with healthy volunteers. This provides the first evidence for the biological occurrence of protein-bound CAPs in vivo and further suggests that free-radical oxidation of polyunsaturated lipids produces hydroxyalkenal carboxylate esters whose gamma-hydroxy-alpha,beta-unsaturated aldehyde functionality and reactivity resemble that of HNE.
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PMID:(Carboxyalkyl)pyrroles in human plasma and oxidized low-density lipoproteins. 943 30

1. Pancreatic bile-salt-dependent lipase has been detected in human plasma where it has the capability to modify normal low- and high-density lipoprotein composition and structure and to reduce the atherogenicity of oxidized low-density lipoprotein (Shamir R, Johnson WJ, Morlock-Fitzpatrick K, Zolfaghari R, Li L, Mas E, Lombardo D, Morel DW, Fisher EA. Pancreatic carboxyl ester lipase: a circulating enzyme that modifies normal and oxidized lipoproteins in vitro. J Clin Invest 1996; 97: 1696-704). 2. In the present study, we investigated the effect of glycation and particularly that of human serum albumin on the activity of bile-salt-dependent lipase. In vitro, bile-salt-dependent lipase activity decreased in the presence of human serum albumin; however, this was less pronounced in the presence of glycated human serum albumin. In vivo, bile-salt-dependent lipase specific activity was about 2-fold higher in the sera of diabetic patients than in the sera of normal subjects. 3. A significant increase in the specific activity of bile-salt-dependent lipase related to the serum level of glycation was observed. The increase in bile-salt-dependent lipase specific activity was not related to the glucose concentration in serum suggesting that glycation of bile-salt-dependent lipase could not be involved in the observed effects. Although the stability of serum bile-salt-dependent lipase was important enough to allow a systemic action of the enzyme on lipoproteins, it could not explain the higher activity of the enzyme in diabetic serum. 4. We concluded that bile-salt-dependent lipase could be helpful against the premature development of atherosclerosis in diabetes.
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PMID:Pancreatic bile-salt-dependent lipase activity in serum of diabetic patients: is there a relationship with glycation? 953 27

To clarify the mechanism of cellular injury through the nonenzymatic reaction of glucose with proteins, we studied the cytotoxic effect of glycated bovine serum albumin on cultured smooth muscle cells in the presence of cupric ion. Glycated proteins were prepared by incubating bovine serum albumin with 0.5 M D-glucose in 0.3 M sodium phosphate buffer at 37 degrees C for 2, 4 and 16 weeks (g-BSA-2, g-BSA-4 and g-BSA-16, respectively). Early glycation products, such as fructosamine, were formed more than two weeks after incubation. However, the immunoreactivity of glycated proteins to anti-AGE antibody was 12-fold higher in g-BSA-16 than in g-BSA-2. Both g-BSA-2 and g-BSA-16 showed a concentration-dependent cytotoxicity in smooth muscle cells in the presence of 80 microM cupric ion by an MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) dye reduction assay and dye exclusion test. Flow cytometry and spectrofluorophotometry using dihydrorhodamine 123 showed that the extracellular generation of oxidants was dose-dependently enhanced with increasing concentrations of g-BSA-2 or g-BSA-16 in the presence of cupric ion. However, no difference was observed in the intracellular generation of oxidants between the presence and absence of glycated proteins by flow cytometry using 2', 7'-dichlorofluorescein diacetate. Cytotoxicity and oxidant generation were prevented by catalase and tiron, but not by superoxide dismutase or mannitol, a hydroxyl radical scavenger. These results indicate that smooth muscle cells may be damaged by reactive oxygen species which are produced extracellularly by the interaction with the early glycation products and cupric ion, and suggest that hydrogen peroxide may be a candidate for reactive oxygen species which contribute to such oxidative damage of smooth muscle cells.
Atherosclerosis 1998 Feb
PMID:Oxidative damage of vascular smooth muscle cells by the glycated protein-cupric ion system. 954 97

Treatment of human umbilical vein endothelial cells (HUVEC) with oxidized low density lipoprotein (ox-LDL, 100 microg/ml) for 24 h increased adhesion of human monocytic Mono Mac 6 cells from 4.8 +/- 0.9% to 17.6 +/- 2.5% (P < 0.001). The effect was dose dependent and first evident at 10 microg/ml ox-LDL. In contrast, adhesion of U937 cells was not significantly increased. Mac-1 (CD11b/CD18), a monocytic counter-receptor for intercellular adhesion molecule-1 (ICAM-1), that also binds to heparin, is present on Mono Mac 6 but not on U937 cells, and may thus explain these differences in adhesion. Consistently, ox-LDL induced a 2-fold upregulation of ICAM-1 surface expression on HUVEC. The presence of maltose-1-phosphate or heparin but not monoclonal antibodies (mAbs) to ICAM-1 reduced adhesion of Mono Mac 6 cells to untreated HUVEC. Combinations of mAbs to ICAM-1 with either maltose-1-phosphate or heparin inhibited Mono Mac 6 adhesion to ox-LDL-stimulated HUVEC by more than 50%, while either alone had no effect. This suggests that two distinct endothelial ligands for Mac-1, inducible ICAM-1 and carbohydrate-decorated heparin-like proteoglycan structures mediate monocytic cell interaction with ox-LDL-treated HUVEC. The stimulating activity in ox-LDL could partly be transfered to bovine serum albumin, while lysophosphatidylcholine or 8-epi prostaglandin F2alpha produced no stimulatory effects. The inhibition of ox-LDL effects with the antioxidant PDTC indicates radicals as possible mediators. In conclusion, we show that oxidatively modified LDL induces adhesion of monocytic cells, which utilize at least two distinct adhesive receptors on endothelium, one being identified as ICAM-1.
Atherosclerosis 1998 Feb
PMID:Monocytic cell adhesion to endothelial cells stimulated by oxidized low density lipoprotein is mediated by distinct endothelial ligands. 954 1


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