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)

Prostaglandins (PG) are highly unsaturated, cyclic fatty acids with 20 carbon atoms which are biosynthesized from dihomo-gamma-linolenic, arachidonic and eicosapentaenoic acids. These fatty acids are either ingested or are biosynthesized from linoleic and linolenic acids, respectively. The PG-precursor fatty acids are liberated from membrane phospholipids by phospholipase A and are converted to prostaglandins by the multienzyme complex PG-synthetase. The activity of the PG-system is influenced by extracellular hormonal, neural and mechanical stimuli and by intracellular factors such as ion-concentration and activity of the enzymes adenyl- and guanylcyclase. Prostaglandins are tissue hormones or autacoids which act on their receptors near their site of synthesis and degradation. The prostaglandin family constitutes a group of more than 10 natural occurring compounds showing a variety of biological actions. In arteries and veins the different PG:s have vasodilating as well as vasoconstricting effects. In addition, they are involved in the regulation of vascular smooth muscle proliferation. Within the kidney PG:s have vascular and tubular actions. They antagonize the effect of ADH, mediate renin secretion and are involved in the control of electrolyte balance. In the regulation of platelet aggregation and platelet adhesion PG:s have opposite functions: Prostacyclin which is synthesized in the vascular wall antagonizes the aggregating action of Thromboxane A2 which is formed in the platelets. A defect or an imbalance in the production of PG:s in the vascular wall, in platelets or in the kidney is assumed to play a pathogenetic role in a variety of cardiovascular and renal diseases such as in hypertension, atherosclerosis, persistent ductus arteriosus and Bartter's syndrome.
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PMID:[Prostaglandins in cardiovascular and renal function. Biochemical, physiological and clinical findings (author's transl)]. 10 97

Metabolism of arachidonic acid (AA) was studied in perfused lungs and kidneys of normal and atherosclerotic rabbits by determination of PGE2, PGF2 alpha and the stable metabolites of PGI2 (6-keto-PGF1 alpha) and TXA2 (TXB2). PGI2 was the main AA metabolite formed by normal lungs and kidneys. Atherosclerosis reduced the formation of PGI2 by about 50 % in both organs. TXA2 formation was similarily decreased in lungs. In kidneys, the decrease in PGI2 formation was accompanied by an increase in PGE2 formation.
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PMID:Atherosclerosis decreased prostacyclin formation in rabbit lungs and kidneys. 38 29

Thromboxane A2 (TxA2) is the main arachidonic acid metabolite in human platelets and exhibits two major activities; stimulation of platelet function, including secretion of platelet-derived storage products, e.g., 5-HT, PDGF, and vasoconstriction. Platelet hyperreactivity is typical for advanced stages of atherosclerosis and is paralleled by elevated circulating thromboxane levels. This is the target for TX-antagonistic compounds. Three classes of selective compounds are available: inhibitors of thromboxane synthase, antagonists of thromboxane receptors, and mixed-type agents. Positive experimental data with all of these compounds are available. However, clinical experience is limited and, in general, not convincing. This review discusses possible reasons for that and suggests that, in particular, the use of combined-type agents as antithrombotics may be superior to acetyl-salicylic acid in several forms of ischemic cardiovascular diseases.
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PMID:[Thromboxane A2 and prevention of cardiovascular diseases]. 129 Feb 97

Thromboxane A2 (TXA2) biosynthesis was studied in healthy subjects, patients with chronic cerebral infarction, patients under chronic aspirin treatment and patients with atrial fibrillation. Urinary 11-dehydro-TXB2, as a major metabolite of TXA2, was measured by radioimmunoassay. The extent of carotid atherosclerosis was determined by B-mode ultrasonography. The mean +/- SD urinary excretion in patients with cerebral infarction and distinct carotid-atherosclerotic lesions (1,725 +/- 239 ng/g creatinine, n = 6) was significantly higher (p less than 0.01) than in healthy subjects (911 +/- 239 ng/g creatinine, n = 44) and patients with cerebral infarction who had no distinct carotid lesion (1,050 +/- 191 ng/g creatinine, n = 6). The urinary excretion of healthy subjects was higher (p less than 0.01) in smokers (1,063 +/- 244 ng/g creatinine, n = 17) than in non-smokers (815 +/- 183 ng/g creatinine, n = 27). Aspirin largely suppressed 11-dehydro-TXB2 excretion (266 +/- 114 ng/g creatinine, n = 7). Three of 5 patients with atrial fibrillation showed very high values. Our results indicated that platelet activation occurs in the atherosclerotic lesions, and that urinary 11-dehydro-TXB2 is the appropriate analytic target for detecting platelet activation.
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PMID:Urinary 11-dehydro-thromboxane B2: a quantitative index of platelet activation in cerebral infarction. 139 73

The influence of a 4-weeks therapy with 500 mg ticlopidine daily on platelet function parameters was examined in 10 male healthy volunteers aged 20-33 years in order to extend the knowledge on the antiplatelet activity of this substance. Ticlopidine significantly (p less than 0.01) affected ex-vivo platelet aggregation induced by ADP and increased platelet sensitivity to the antiaggregatory action of PGI2. Generation of TXB2 from endogenous substrate during spontaneous clotting of blood (serum-TXB2), conversion of exogenous radiolabelled arachidonic acid into TXB2 and MDA-formation in isolated platelets were unaffected by the treatment. The TXB2-level in plasma of volunteers, however, was decreased, after administration of the drug. The diminished alpha-granule content liberation (beta-thromboglobulin: p less than 0.01; PDGF: p less than 0.01; PF4 not significant) indicates that ticlopidine induces a decrease in platelet activity. The beneficial effect on release reaction is not associated with a decrease in TXA2-formation. Our results demonstrate that ticlopidine inhibits platelet activity, especially the PDGF-release. These results confirm the value of this drug in the prevention of atherosclerosis and its thromboembolic complications.
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PMID:Ticlopidine and platelet function in healthy volunteers. 161 96

In rat hepatocyte cultures daltroban reduced 14C-acetate incorporation stronger into cholesterol (CH) esters than into free CH. Further data suggest that the reduction of cellular sterols by daltroban is independent from its TXA2 receptor antagonistic activity and caused by reduced capacity of ACAT depending CH esterification. In rabbits fed CH-enriched diet treatment with daltroban led to an inhibition of platelet aggregation and to a significant reduction of progression of atherosclerosis. Both reduced CH esterification and TXA2 receptor antagonism may contribute to the diminution of progression of atherosclerosis by daltroban.
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PMID:Effects of daltroban, a thromboxane (TX) A2 receptor antagonist, on lipid metabolism and atherosclerosis. 163 87

Reduced prostacyclin (PGI2) production by the vascular wall may play an important role in the pathogenesis of vascular lesions such as atherosclerosis. The present study was undertaken to evaluate the effect of vitamin E on the production of PGI2 and other prostaglandins (prostaglandin E2 [PGE2], thromboxane A2 [TXA2], and 15-hydroxyeicosatetraenoic acid [15-HETE]) by bovine aortic endothelial cells cultured in a high concentration of glucose (300 mg/dL). Compared with endothelial cells cultured in 100 mg/dL glucose, the production of PGI2 and other prostaglandins, except 15-HETE, was significantly reduced in cultures containing 300 mg/dL glucose when stimulated by histamine, the Ca2+ ionophore, A23187, or human plasma-derived serum (PDS). The addition of vitamin E to each stimulant significantly restored the production of PGI2, PGE2, and TXA2, products of the cyclo-oxygenase pathway, in aortic endothelial cells cultured in 300 mg/dL glucose. This effect of vitamin E on the stimulation of prostaglandin production was generally specific for D-alpha-tocopherol, but not for the other vitamin E analogs tested. However, vitamin E and the stimulants had no effect on the production of 15-HETE, a product of the lipoxygenase pathway. Moreover, vitamin E alone, without stimulants, did not affect prostaglandin production in cultured bovine aortic endothelial cells. These results suggest that vitamin E may restore reduced PGI2, PGE2, or TXA2 production by bovine aortic endothelial cells cultured in a high concentration of glucose. It seems likely that vitamin E may restore depressed PGI2 production by the vascular wall in hyperglycemic conditions such as those seen in patients with diabetes mellitus.
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PMID:Vitamin E restores reduced prostacyclin synthesis in aortic endothelial cells cultured with a high concentration of glucose. 164 Aug 48

The effects of nifedipine, diltiazem, and Paeonia lactiflora Pall (PLP) on serum lipids. Plasma lipid peroxides (LPO), TXB2, and 6-keto-PGF1 alpha in cholesterol-fed rabbits have been investigated. Oral administration of nifedipine (15 mg/kg.d), diltiazem (30 mg/kg.d), and PLP (5 g/kg.d) caused 60.8%, 45.2%, and 74.2% reduction in the area of atherosclerosis in the aorta respectively. The levels of plasma LPO and TXB2 and the contents of cholesterol, phospholipid, and calcium in the intimal-media of the aorta in the treated groups were significantly lower than those in the cholesterol group, but the level of plasma 6-keto-PGF1 alpha in the treated groups was significantly higher. The appearance of cholesterol-induced TXB2 elevation and 6-keto-PGF1 alpha decrease in the treated groups was delayed. There are positive correlation between plasma TXB2 and the followings: serum lipids, plasma LPO, and the content of calcium in the intimal-media of the aorta, and the percentage of area of lesion in the aorta, while plasma 6-keto-PGF1 alpha showed significantly negative correlation with the above data. TXB2/6-keto-PGF1 alpha was found to be positively correlated with the percentage of lesion area of the aorta. It was shown that Ca2+ metabolism plays an important role in thromboxane, prostaglandin, and LPO metabolism. In conclusion, the inhibition of LPO production and regulation of TXA2-PGI2 balance may be one of the main mechanisms of the antiatherogenic effects of calcium antagonists and PLP.
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PMID:[The effects of nifedipine, diltiazem, and Paeonia lactiflora Pall. on atherogenesis in rabbits]. 187 9

An increased lipid peroxides and a decreased production of prostacyclin have been shown in advanced atherosclerotic lesions and plasma. Our purpose was to determine whether the similar findings could be observed in cultured endothelial cells, and whether antioxidants could protect the cell against peroxide injury. In these experiments we have used bovine aortic endothelial cells in culture to address the issue of hyperlipidemia-induced arterial damage. Results of the present study showed that different concentration of hyperlipidemic sera from atherogenic rabbits induced a time- and dose-dependent alteration in the production of prostacyclin and levels of lipid peroxides in endothelial cells. Endothelial cells incubated with hyperlipidemic serum increased prostacyclin generation significantly during the initial stages and then continuously decreased. When endothelial cells were incubated for 36 h, TXA2 generation was also impaired and at the same time the cellular lipid peroxides content increased. There was a positive correlation between the concentration of hyperlipidemic serum and lipid peroxides and an inverse correlation with prostacyclin synthesis. The medium supplemented with antioxidant selenium or vitamin E showed a significant decrease in lipid peroxides and an increase in prostacyclin synthesis. These results suggest that both hyperlipidemic serum and lipid peroxides injury endothelial cells and inactivate prostacyclin synthetase, resulting in a decrease of prostacyclin production, while antioxidants have a protective effect. We conclude that the increase in lipid peroxides in association with hyperlipidemia results in alteration of prostacyclin synthesis that may play an important role in the pathogenesis of atherosclerosis.
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PMID:Effect of hyperlipidemic serum on lipid peroxidation, synthesis of prostacyclin and thromboxane by cultured endothelial cells: protective effect of antioxidants. 267 46

In 35 pigs atherosclerosis was induced by balloon abrasion and a diet containing 2% (w/w) cholesterol and 7% (w/w) lard fat. After 4 months of induction nine animals were killed (I) for analysis of the extent of atherosclerosis, while the diet of the other 26 pigs was changed to a low cholesterol diet containing either 9% (w/w) lard fat (L), 9% (w/w) fish oil (F) or 4.5% (w/w) lard fat and 4.5% (w/w) fish oil (LF). This diet was continued for 3 months to induce regression of atherosclerosis. The cholesterol-rich diet increased plasma total cholesterol, but did not affect plasma triglycerides. Low-cholesterol feeding decreased plasma total cholesterol in all three groups, but triglycerides only in LF and F. Lipid infiltration of the aortic wall was similar in I, L, LF and F. In the denudated coronary arteries of I mean luminal encroachment was 11 +/- 2%. This was similar in L (13 +/- 4%) but significantly lower (P less than 0.05) in LF (6 +/- 2%) and in F (3 +/- 1%). In the non-abraded coronary arteries of I mean luminal encroachment was 1.3 +/- 0.3%. For F and LF similar values were found, but in L there was an increase to 11 +/- 3% during low-cholesterol feeding. ADP-induced platelet aggregation was lower in LF and F than in L. Thromboxane A2 production was only reduced in F, while the production of the weak thromboxane A3 agonist was larger in F than in LF. It is concluded that fish oil retards the progression of and causes regression of coronary atherosclerosis.
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PMID:Mackerel oil and atherosclerosis in pigs. 280 83


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