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 effects of experimental coronary atherosclerosis on myocardial high energy phosphates and regional coronary perfusion and oxygen delivery were studied. Hypercholesterolemic (HC) New Zealand white rabbits developed mild to moderate coronary vascular disease in 4 months when serum cholesterol levels were maintained at 1500--2000 mg/dl. Resting left ventricular levels of creatine phosphate, adenosine triphosphate (ATP), and the cellular energy charge were unaltered after 2 months of diet but were decreased after 4 and 6 months. Tissue lactate and the lactate/pyruvate ratio were increased after 4 months, suggesting mild tissue ischemia. The regional blood flow rate was measured in rabbits given pentobarbital after 6 months of diet using labeled microspheres, and the response to stress was tested after 5 minutes of hypoxic ventilation (5% O2/N2). The percentage of cardiac output to subendocardium (endo) and subepicardium (epi) in HC rabbits and that in control animals were similar at rest, but unlike that of control animals, the endo perfusion did not increase significantly in HC animals during hypoxic stress. Baseline regional left ventricular oxygen deliveries were similar between groups, but the baseline endo/epi oxygen delivery ratio was reduced in HC rabbits. In control rabbits hypoxia did not alter total O2 delivery, and the endo/epi oxygen delivery ratio was constant, whereas hypoxia in HC animals produced a decrease in total oxygen delivery and a further decrease in the endo/epi oxygen delivery ratio. Thus, moderate long-term coronary occlusive disease produced alterations in the distribution of coronary perfusion that are similar to those after acute partial occlusion, ie, selective reductions in blood flow and oxygen delivery to subendocardium. These results may relate to the pathogenesis of subendocardial infarction in man, which often occurs in the absence of complete coronary occlusion.
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PMID:Regional coronary perfusion and bioenergetics in experimental atherosclerosis. 736 55

Agents inhibiting calcium deposition into arteries are known to suppress atherosclerosis in animals. However, the precise role of calcium in atherogenesis is unknown. In this study, the specific Ca2+-antagonist lanthanum was used to attempt suppression of experimental atherosclerosis and to gain more insight into the possible effects of calcium on atherogenesis. Rabbits were fed an atherogenic diet with and without increasing doses of LaCl3. All cholesterol-fed rabbits showed marked increases in serum cholesterol and ca2+. Untreated atherogenic animals revealed pronounced gross and microscopic atherosclerosis and striking increases in the aortic content of cholesterol, collagen, "elastin," and calcium as well as of elastin calcium, polar amino acids, and cholesterol. With increasing LaCl3 dosage these abnormalities progressively decreased and were completely abolished at the highest dose. The ingested La3+ was absorbed only in small quantities and had no discernible effect on the calcium and connective tissue content of bone, skin, lung, heart, and skeletal muscle nor on myocardial function (left ventricle pressure and left ventricle dp/dt) or myocardial and muscle content in ATP and creatine phosphate. The data suggest that shifts in arterial Ca2+-distribution may play a decisive part in atherogenesis, and provision of arterial calcium homeostasis by La3+ a pivotal role in its prevention, despite hypercholesteremia. Other inhibitors of calcium deposition into arteries may exert their protective effect by similar mechanisms. However, a direct inhibition of atherogenesis by La3+ cannot entirely be ruled out in this study, although no direct effects of La3+ on tissue metabolism have as yet been reported.
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PMID:Suppression of experimental atherosclerosis by the Ca++-antagonist lanthanum. Possible role of calcium in atherogenesis. 736 47

Study of the key mechanisms, metabolism regulators, showed that in the blood of patients with atherosclerosis the NAD/NAD . N ratio decreases by 59.8% and the NAD+ concentration by 44%, while the NAD . N content increases by 56.7%. In the nicotinamide adenine dinucleotide system there is a general tendency tomards accumulation:the concentration of NADP+ grows by 218.6% and that of NADP . N by 12.9%. A marked increase in the content of incompletely oxidized products is determined: lactic acid by 37.4%, alpha-glycerophosphate by 49.8%, dihydroxyacetone phosphate by 155%, oxaloacetate by 131% in the presence of lactate dehydrogenase and malate dehydrogenase activation. The detected changes are evidence of tissue energy debt in atherosclerosis, they reflect the character of metabolic acidosis formation and point to the presence of conditions for intensified liposynthesis.
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PMID:[Content of nicotinamide coenzymes, metabolites and the NAD-dependent dehydrogenase activity in the blood in arteriosclerosis]. 737 12

Precipitates of calcium phosphate in coronary arteries always indicate the presence of atherosclerosis. The mass of these precipitates is related to the severity of atherosclerosis. To determine the accuracy of electron beam computed tomographic (CT) mass estimates, we imaged 21 human hearts inside an anthropomorphic chest phantom using an Imatron C-100 electron beam CT scanner (Imatron, San Francisco, CA). We then incinerated the 63 imaged coronary arteries and weighed the mineral ash. We calculated the mass estimates from the images using an algorithm derived from a model that assumes simple radiographic properties of the coronary arteries. We also calculated the currently used coronary calcium score for each artery. Although both the mass estimates and the scores correlated with the actual mass of the incinerated specimens (r = .97 and r = .93), the correlation with the mass estimates was better (P = .02; William's test). The regression equation relating the actual mass to the mass estimates was y = 1.37 x + 14, indicating that the CT mass estimates consistently underestimate actual coronary calcium phosphate mass. We conclude that relative mass estimates using electron beam CT scanning are accurate and that both these and the currently employed calcium scores reflect the actual mass of precipitated calcium phosphate in diseased coronary arteries.
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PMID:Accurate coronary calcium phosphate mass measurements from electron beam computed tomograms. 754 56

Twelve adults (age 32-61 years) with essential hypertension were recruited from the outpatient clinics of National Defense Medical College hospital to serve as subjects in the present study. They were treated with nilvadipine, a Ca-antagonist, 4 mg b.i.d. for 4 weeks. LDL samples were isolated by ultracentrifugation at the beginning (week 0) and at the end (week 4) of the treatment regimen. The formation of conjugated dienes was measured by incubating 100 micrograms of LDL protein with 2 mumol CuSO4 in 2 ml phosphate buffered saline (PBS). There were no significant differences between lipids levels, composition and anti-oxidant levels of LDL at weeks 0 and 4. The lag time of LDL oxidation was 71.1 +/- 11.3 min at week 0 and 81.3 +/- 13.2 min at week 4 (p < 0.05). In vitro studies of LDL oxidation, evaluated by thiobarbituric acid reactive substances (TBARS) and by agarose electrophoretic mobility, indicated that nilvadipine inhibited the oxidative modification of LDL while amlodipine, used as control, did not. Nilvadipine, a lipophilic Ca-antagonist, significantly prolonged the lag time of conjugated diene formation of LDL by 12.6% but amlodipine, a hydrophilic Ca-antagonist, had no major effect on LDL oxidation. These results suggest that Ca-antagonists are effective for the prevention of atherosclerosis but the effect is dependent upon the lipophilicity of the drugs.
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PMID:Effects of Ca-antagonists on oxidative susceptibility of low density lipoprotein (LDL). 758 10

It has been generally accepted that oxidized low density lipoprotein (LDL) plays an important role in atherogenesis. However, oxidized LDL was not detected in patients' blood and the extent of LDL oxidation in vivo is unknown. We have suggested that LDL oxidation may lead to a formation of covalent links between lipids and apolipoprotein B. LDL were oxidized by copper ions, 2,2'-azobis-(2-aminopropane hydrochloride), sodium hypochlorite or by incubation with macrophages. Oxidized LDL were delipidated by repeated extraction with organic solvents. After mild alkaline hydrolysis protein-bound sterols were identified colorimetrically and by high-performance liquid chromatography. Protein-bound phospholipid residues were detected by nuclear magnetic resonance and colorimetric determination of phosphate. Using radiolabeled lipids it was also shown that free and esterified cholesterol, phospholipids, as well as triglyceride and free fatty acid residues can form covalent bonds with apolipoprotein B. The ability of lipids to bind to apolipoprotein B correlates with the degree of unsaturation of their fatty acids and depends on the nature of polar head of phospholipids. When LDL were oxidized with copper ions, the content of protein-bound lipids increased gradually up to 24 h of incubation, while the levels of conjugated dienes, hydroperoxides and thiobarbituric acid-reactive substances changed in varying manners. It has been demonstrated that the content of protein-bound sterols in multiple-modified desialylated LDL of patients with coronary atherosclerosis is higher than that in native LDL. Our results suggest that the level of protein-bound lipids may be a marker of LDL oxidation and can be used to evaluate the association of lipoprotein oxidation and atherogenesis.
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PMID:Apolipoprotein B-bound lipids as a marker for evaluation of low density lipoprotein oxidation in vivo. 767 72

Adenosine triphosphate (ATP), a co-transmitter in sympathetic nerves and released from platelets, has recently been shown to stimulate growth of vascular smooth muscle cells. It might therefore contribute to the development of vascular hypertrophy seen in hypertension and atherosclerosis. We aimed at characterising the receptor mediating this mitogenic effect in rat aorta smooth muscle cells. The potency of agonists indicates a P2 purinoceptor since ATP > or = ADP >> AMP, adenosine. The P2x-receptor subtype, which is responsible for ATP induced vasoconstriction in rat aorta, does not mediate the mitogenic effect since alpha, beta-methyleneATP had no effect and beta, gamma-methyleneATP had lower potency than ATP. The P2Y-receptor subtype was excluded since the selective agonist 2-methylthioATP had weak effect with lower potency than ATP. When we studied the involvement of other nucleotides similar effects were seen of the purines ATP, GTP and ITP; also the pyrimidine UTP had powerful mitogenic effects (Emax = 52% of ATP) with similar potency. Nucleotides with fewer phosphate groups showed a stepwise fall in mitogenic effect. This indicates involvement of a nucleotide-receptor (P2U). Ap4A were of equal potency and effect as ATP. There was strong correlation between the mitogenic effects of the nucleotides and analogues with both 45Ca(2+)-influx and inositol phosphate (IP) production, indicating that they may participate in mediating the mitogenic response. This is the first study describing the potencies for the mitogenic effects of the selective ATP-analogues and other nucleotides in vascular smooth muscle cells. The receptor characterisation indicates a nucleotide-receptor similar to the receptor which stimulates 45Ca(2+)-influx and inositol phosphate-formation in rat aorta smooth muscle cells. Substances related to ATP such as GTP, ITP, UTP and Ap4A which also can be released extracellularly in vivo stimulate mitogenesis of rat aorta smooth muscle cells through the same receptor.
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PMID:Characterisation of an ATP receptor mediating mitogenesis in vascular smooth muscle cells. 778 5

In this work, an x-irradiation/high fat/high cholesterol diet-induced atherogenic model was invoked to examine the effects of severe diffuse atherosclerosis on myocardial metabolism in the in vivo porcine heart. This model was studied using spatially localized 31P-nuclear magnetic resonance (NMR) to monitor pH and the levels of inorganic phosphate, phosphomonoesters, creatine phosphate, and adenosine triphosphate as a function of workload transmurally in control swine and in animals suffering from chronic ischemic heart disease. These preliminary studies revealed that the development of severe atherosclerosis and the accompanying chronically diseased state produce changes in high energy phosphates and that increases in rate pressure products result in demonstrable signs of ischemia in the myocardium which span the entire left ventricular wall. Ischemic changes include a global increase in inorganic phosphate and corresponding decreases in creatine phosphate, ATP, and pH. Importantly, changes in intracellular pH are noted with even the slightest increase in workload suggesting that these diseased hearts display elevated glycolytic activity. By challenging these animals with increased cardiac workload, we directly visualize how the chronically compromised heart responds to severe oxygen challenges in a clinically relevant model of this situation.
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PMID:31P-nuclear magnetic resonance studies of chronic myocardial ischemia in the Yucatan micropig. 781 9

The oxidative modification of low-density lipoprotein by macrophages may be an important mechanism in the pathogenesis of atherosclerosis. The human monocytic leukaemia cell line THP-1, when stimulated with phorbol ester, shares many properties with human monocyte-derived macrophages. Oxidation of LDL by these cells was characterised by depletion of alpha-tocopherol, increases in thiobarbituric acid reactive substances and increases in electrophoretic mobility. The LDL particles were also converted to a form which increased accumulation of cholesteryl esters within macrophages. The oxidative mechanism appeared to be dependent upon the presence of thiols in the cellular medium. Oxidation of LDL by THP-1 macrophages, and production of thiols by these cells, were dependent upon the presence of L-cystine in the medium. Furthermore, cellular oxidation of LDL could be partially mimicked by the addition of cysteine to Hams F10 medium. Macrophage-independent oxidation of LDL, mediated by the addition of copper ions, was inhibited by cystine and cysteine in phosphate buffered saline, but not in Hams F10 medium. The glutathione content of THP-1 macrophages was also dependent upon the presence of cysteine or cystine in the medium, but inhibition of glutathione synthesis by buthionine sulfoximine did not prevent the production of thiols or the oxidation of LDL by THP-1 macrophages.
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PMID:Human (THP-1) macrophages oxidize LDL by a thiol-dependent mechanism. 888 36

The objective of the study was to characterize unesterified cholesterol particles in human aorta and to correlate the findings with the severity of aortic atherosclerosis. Human tissues were processed under conditions that preserve deposits of unesterified cholesterol agglomerates. Filipinfluorescence was determined by using a novel triple band pass filter. The pattern of unesterified cholesterol deposits was age related and correlated with the severity of atherosclerosis. We found three types of deposits: 1), small spherulites (3 to 5 mu), which were depicted in both the media and intima in individuals as early as age 16, and which, in more advanced ages, showed an increase in density and a tendency to aggregate extracellularly throughout the intima in clusters; 2), elongated structures (10 to 30 mu in the middle zone of the intima), the density of which was directly related to the severity of atherosclerosis; and 3), large (100 mu), irregular deposits found mainly in the core of atherosclerotic plaques. The medium size deposits, compared with those found in the core of atherosclerotic plaques, retain their overall size (10 to 30 mu), uniformity (oval elongated), and localization (middle zone of the intima). On the basis of these observations we hypothesize cholesterol deposition in two stages of aggregation: 1), early degradation of infiltrating low density lipoprotein particles forming unesterified cholesterol-rich vesicles in the vessel wall, followed by aggregation to spherulites in the lower part of the intima; and 2), more massive agglomeration of particles containing unesterified cholesterol and calcium phosphate in the midzone of the intima. Because in the second stage of aggregation the transition of cholesterol to the solid state has already occurred, it is irreversible.
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PMID:Distribution of unesterified cholesterol-containing particles in human atherosclerotic lesions. 785 23


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