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)

It was shown that the action of phospholipase A2 on low density serum lipoproteins (LDL) in the presence of serum albumin led to decrease in the floatation coefficient. Lipase hydrolyzed LDL triglycerides after pretreatment of the latter with phospholipase A2. Due to the action of lipases the LDL residue loses its solubility and the cholesterol-rich precipitate forms. The loss of solubility of lipoproteins treated with lipases and proteinases may occur in vivo, underlying athermao formation, i.e. can thus serve as one of the factors in the pathogenesis of atherosclerosis.
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PMID:[Action of lipases on low-density serum lipoproteins]. 19 43

Molecular graphics and molecular mechanics techniques have been used to study the mode of ligand binding and mechanism of action of the enzyme phospholipase A2. A substrate-enzyme complex was constructed based on the crystal structure of the apoenzyme. The complex was minimized to relieve initial strain, and the structural and energetic features of the resultant complex analyzed in detail, at the molecular and residue level. The minimized complex was then used as a basis for examining the action of the enzyme on modified substrates, binding of inhibitors to the enzyme, and possible reaction intermediate complexes. The model is compatible with the suggested mechanism of hydrolysis and with experimental data about stereoselectivity, efficiency of hydrolysis of modified substrates, and inhibitor potency. In conclusion, the model can be used as a tool in evaluating new ligands as possible substrates and in the rational design of inhibitors, for the therapeutic treatment of diseases such as rheumatoid arthritis, atherosclerosis, and asthma.
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PMID:Modeling of substrate and inhibitor binding to phospholipase A2. 140 62

Modification of the low density lipoprotein (LDL) core or surface lipids were shown to affect the cellular uptake of the lipoproteins and hence the formation of foam cell macrophages. In the present study phospholipase A2 treatment of LDL was shown to produce negatively charged lipoprotein with increased content of lysolechitine. This modified lipoprotein was taken up and degraded by J-774 A.1 macrophage-like cell line at enhanced rate (up to 97% when 10 units/ml of PLase A2 was used) in comparison to control LDL. This effect of PLase A2 was enzyme dose dependent. Competition experiments revealed that the uptake of PLase A2-LDL by the macrophages was specific and was mediated via the LDL receptor. Since PLase A2 was found to exist in various tissues, thus the production of PLase A2-LDL under certain pathological conditions can potentially contribute to foam cell formation and accelerated atherosclerosis.
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PMID:Phospholipase A2-modified LDL is taken up at enhanced rate by macrophages. 159 85

The immunoreactivity of human apolipoprotein B (apo B) towards 5 monoclonal antibodies was studied by enzyme immunoassay in native and in vitro oxidized low density lipoproteins (LDL). LDL oxidative modifications were obtained by incubation with either copper ions or an association of lipoxygenase and phospholipase A2. The monoclonal antibodies used in the inhibition analysis were directed to epitopes located in the amino-terminal region (1D1), in the middle part (2D8, L7, 4G3) and in the carboxy-terminal region (L3) of the apo B molecule. The results demonstrated that the immuno-reactivity of 1D1 epitope was little affected by LDL oxidation with copper ions or lipoxygenase plus phospholipase A2, whereas the immunoreactivity of the other epitopes were markedly decreased by these LDL modifications. Immunoreactivity changes were more important in L3 and L7 epitopes than in 2D8 and 4G3 epitopes. Since it is known that L3 and L7 epitopes are located in apo B domains rich in lipid-associated peptides whereas 1D1 is in a domain poor in such peptides, these results suggest a relationship between the lipid environment of an apo B epitope and its susceptibility to alteration by LDL oxidation.
Atherosclerosis 1991 Jul
PMID:Resistance to LDL oxidative modifications of an N-terminal apolipoprotein B epitope. 172 77

The effects of vitamin D3 on the production of prostacyclin (PGI2) by cultured rabbit vascular smooth muscle cells (VSMCs) were investigated. PGI2 synthesis by VSMCs was significantly increased in the presence of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and 1 alpha hydroxyvitamin D3 (1 alpha(OH)D3) at 48 hours [1,25(OH)2D3 greater than 1 alpha(OH)D3]. Physiological concentration of 1,25(OH)2D3 (10(-10) M) significantly increased the synthesis of PGI2. Further, we observed that treatment with 1,25(OH)2D3 significantly induced the activity of cyclooxygenase without changing the activity of phospholipase A2. These findings suggest that the mechanism of action of 1,25(OH)2D3 on the synthesis of PGI2 is mediated by the cyclooxygenase pathway. It seems possible that vitamin D3 is a vasoactive agent and may play a protective role in the development of atherosclerosis.
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PMID:Vitamin D3 stimulates the production of prostacyclin by vascular smooth muscle cells. 177 35

The effect of cigarette smoking on the levels of platelet-activating factor-like lipid(s) (PAF-LL) in plasma lipoproteins was studied. The subjects were 10 healthy male non-smokers (24 +/- 1.4 years old) and 13 healthy male habitual smokers (23 +/- 1.3 years old). Fasting venous blood was obtained and basal levels of PAF-LL in plasma lipoproteins were estimated. The acute effect of cigarette smoking was also studied in smokers. Plasma lipoproteins were separated by ultracentrifugation. Lipids were extracted and separated by thin-layer chromatography. The fraction with the same migration as authentic PAF was recovered and was shown to cause aggregation of human polymorphonuclear neutrophils. This activity was identified as PAF-LL because it was inactivated by phospholipase A2 and was blocked by CV-3988, an antagonist of the PAF receptor. PAF-LL was detected in LDL and HDL, but not in VLDL or in lipoprotein-deficient plasma. The levels of PAF-LL in LDL in non-smokers, and in smokers before and after smoking were 13 +/- 7.5, 16 +/- 14.9 and 190 +/- 179.0 pg/ml, and those in HDL were 12 +/- 5.2, 40 +/- 40.0 and 235 +/- 205.1 pg/ml, respectively. The values in both LDL and HDL in smokers increased significantly after smoking (P less than 0.05). After 30 min, the levels had returned almost to the pre-smoking levels. We conclude that cigarette smoking induces an increase in the levels of PAF or closely related lipid(s) in LDL and HDL, which may be related to smoking-induced atherosclerosis.
Atherosclerosis 1991 Mar
PMID:Effect of cigarette smoking on the levels of platelet-activating factor-like lipid(s) in plasma lipoproteins. 187 24

Phagocytes (P), i.e. neutrophils, monocytes and macrophages, may be involved as well as reactive oxygen species (ROS) in the initiation and development of atherosclerosis. Evidences for this assumption are the following; P and ROS are both able to damage endothelial cells whose dysfunction is crucial in the etiology of atherosclerosis. ROS generated by endothelial cells, smooth muscle cells or mainly blood cells such as neutrophils but also monocytes platelets and erythrocytes, peroxide directly endothelial cell membranes. Damage to cell membranes can be induced by P that adhere to, and release on endothelial cells large amounts of proteolytic and lipolytic enzymes. ROS can also induce formation in the blood of lipoperoxides which are often included in LDL (low density lipoproteins). These modified LDL are cytotoxic, possess phospholipase A2 activity and are recognized by the LDL scavenger receptor which is on the monocyte-macrophage membrane. The modified LDL are also immunogenic inducing formation of autoantibodies directed against them and normal LDL. Modified LDL and LDL immune complexes can be ingested by monocytes leading to foam cells and ROS. The damaged endothelial cells have an increased permeability to macromolecules, synthetize chemotactic factors, decrease their prostacyclin production and favour the adherence of neutrophils and monocytes to their surface. All these factors could increase ROS production and lipid peroxidation amplifying intra and extra-cellular accumulation of lipoperoxides in vascular walls. The ability of ROS and P to damage endothelial cells, to induce lipid peroxidation and thus to be involved in atherosclerosis relies on in vitro experimental results.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Oxygen, phagocytic cells and atheroma]. 265 11

A remarkable variation in monocyte activation among individuals was observed when blood from different people was incubated with lipopolysaccharides. To elucidate this phenomenon, we studied intracellular signals associated with monocyte activation. This was done by measuring induced thromboplastin synthesis. An inhibitor of phospholipase A2 blocked the lipopolysaccharide induced synthesis of thromboplastin. Thus, release of arachidonic acid (20: 4) seemed to be necessary to activate the monocytes. Nordihydroguaiaretic acid, a lipoxygenase inhibitor, had no effect on the monocyte activation in subjects with a low response to lipopolysaccharides (low responders); this contrasted with nearly 80% inhibition in individuals with very sensitive cells (high responders). Taking aspirin raised monocyte activation by an average of 50%, this was caused by the effect of aspirin on the platelets. Platelets enhanced the lipopolysaccharide activation of monocytes 2-3 fold. The high response phenomenon was partially due to platelets. When platelets in the blood of high responders were substituted with platelets from low responders, the monocyte activation fell by up to 70%. Fatty acids seemed to play a central role in the activation of monocytes. Intake of cod liver resulted in significant reduction of induced thromboplastin synthesis. It is suggested that those who are high responders may be more susceptible to developing atherosclerosis.
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PMID:Fatty acids, platelets and monocytes. Something to do with atherogenesis. 292 3

Oxidative damage to the vascular endothelium may play an important role in the pathogenesis of atherosclerosis and aging, and may account in part for reduced vascular prostacyclin (PGI2) synthesis associated with both conditions. Using H2O2 to induce injury, we investigated the effects of oxidative damage on PGI2 synthesis in cultured endothelial cells (EC). Preincubation of EC with H2O2 produced a dose-dependent inhibition (inhibitory concentration [IC50] = 35 microM) of PGI2 formation from arachidonate. The maximum dose-related effect occurred within 1 min after exposure although appreciable H2O2 remained after 30 min (30% of original). In addition, H2O2 produced both a time- and dose-dependent injury leading to cell disruption, lactate dehydrogenase release, and 51Cr release from prelabeled cells. However, in dramatic contrast to H2O2 effects on PGI2 synthesis, loss of cellular integrity required doses in excess of 0.5 mM and incubation times in excess of 1 h. The superoxide-generating system, xanthine plus xanthine oxidase, produced a similar inhibition of PGI2 formation. Such inhibition was dependent on the generation of H2O2 but not superoxide in that catalase was completely protective whereas superoxide dismutase was not. H2O2 (50 microM) also effectively inhibited basal and ionophore A23187 (0.5 microM)-stimulated PGI2 formation. However, H2O2 had no effect on phospholipase A2 activity, because ionophore A23187-induced arachidonate release was unimpaired. To determine the effects on cyclooxygenase and PGI2 synthase, prostaglandin products from cells prelabeled with [3H]arachidonate and stimulated with ionophore A23187, or products formed from exogenous arachidonate were examined. Inhibition of cyclooxygenase but not PGI2 synthase was observed. Incubation of H2O2-treated cells with prostaglandin cyclic endoperoxide indicated no inhibition of PGI2 synthase. Thus, in EC low doses of H2O2 potently inhibit cyclooxygenase after brief exposure whereas larger doses and prolonged exposure are required for classical cytolytic effects. Surprisingly, PGI2 synthase, which is known to be extremely sensitive to a variety of lipid peroxides, is not inhibited by H2O2. Lipid solubility, enzyme location within the EC membrane, or the local availability of reducing factors may explain these results, and may be important determinants of the response of EC to oxidative stress.
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PMID:Effect of hydrogen peroxide on prostaglandin production and cellular integrity in cultured porcine aortic endothelial cells. 299 39

A rat aortic explant culture system was developed for the investigation of the effects of hydrocortisone (HC) and the glucocorticoid antagonist, RU486, on prostacyclin (PGI2 synthesis. HC, but not aldosterone, progesterone, 17 beta-estradiol, or testosterone, inhibited spontaneous, epinephrine-stimulated and U46619 (an analog of thromboxane A2)-stimulated PGI2 synthesis by cultured aortic explants in a concentration- and time-dependent manner. Adequate inhibition of aortic explant PGI2 synthesis by physiological concentrations of HC was achieved after an 18-h culture. An 18-h time course was employed in subsequent experiments. In contrast, HC had no effect on arachidonic acid-stimulated PGI2 synthesis. Protein synthesis inhibitors, actinomycin D and cycloheximide, had no effect on the inhibitory action of HC on epinephrine- and U46619-induced release of PGI2. They exerted a direct inhibitory effect on aortic PGI2 synthesis. Arachidonic acid stimulated PGI2 release by the explants and was unaffected either by HC or by treatment with cycloheximide or actinomycin D. RU486 blocked the inhibitory action of HC on aortic PGI2 synthesis in a dose-dependent manner. Thus, the inhibitory effect of HC on vascular PGI2 synthesis is probably mediated through an inhibition of phospholipase A2 and not cyclooxygenase or other PGI2 synthase systems; furthermore, this inhibitory effect is not dependent upon de novo protein synthesis. RU486 antagonizes the inhibitory effect of HC. The inhibition of vascular PGI2 by hydrocortisone has implications in the pathogenesis of steroid-related hypertension and atherosclerosis and the antiinflammatory effect of steroids.
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PMID:Inhibition by hydrocortisone of prostacyclin synthesis by rat aorta and its reversal with RU486. 308 61


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