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)

Serum lipids and lipoproteins and various lipid fractions in the aorta were compared in spontaneously-occurring and cholesterol-induced atherosclerosis of rhesus monkeys. A group of 30 normal monkeys were also studied. Serum cholesterol, total phospholipid and triglyceride values in spontaneous atherosclerosis were similar to normal, but were significantly elevated in cholesterol-induced atherosclerosis. Fractionation of the major phospholipids in animals with spontaneous atherosclerosis showed increased PC with decreased LPC and SP + LPE, while PE was elevated and SP + LPE diminished in cholesterol-induced atherosclerosis. Beta-lipoproteins were markedly increased in cholesterol-induced atherosclerosis, but remained normal in spontaneous atherosclerosis. Among the aortic lipid, PC and PE were significantly elevated in spontaneous atherosclerosis, but in cholesterol-induced atherosclerosis all the neutral lipids were raised, together with a specific rise of PC and decrease of SP + LPE. These observations tend to indicate that the mechanism of atherosclerosis production in the two states greatly varies.
Atherosclerosis
PMID:Serum and aortic lipid profiles in spontaneous and cholesterol-induced atherosclerosis in Rhesus monkeys. 115 69

Of 100 arteriographically examined, hospitalized, male patients, those without myocardial infarctions were divided into the following categories: zero-, one-, two-, and three-vessel disease; patients diagnosed with myocardial infarction were classified separately. The fasting plasma samples from these patients were examined for concentrations of triglycerides and total cholesterol, lipoprotein profile, lecithin: cholesterol acyltransferase (LCAT) activity, and lysolecithin (LPC) concentration. Those parameters in this group which are commonly determined were consistent with the clinical classification of these patients. Of those remaining parameters, the LCAT activity was increased as the severity of coronary atherosclerosis increased and the changes in the activity of this enzyme were appropriately reflected by increases in LPC concentration and decreases in the proportion of the plasma cholesterol unesterified. The results of this study suggest that increased, rather than decreased, plasma LCAT activity and increased LPC concentrations are characteristic of coronary atherogenesis. The plasma concentrations of LPC observed in these atherosclerotic patients are more than sufficient to qualify this substance for its previously proposed roles of mediator of transmembrane diffusion of LDL and as an inhibitor of platelet aggregation.
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PMID:Lecithin: cholesterol acyltransferase and lysolecithin in coronary atherosclerosis. 346 3

Cardiovascular (CV) risk factors change over time with the emergence of clinically recognizable abnormalities (obesity, hypertension and hyperlipoproteinemia) in the second and third decades of life. A cohort of 286 subjects, aged 11-15 in 1973-74 were reexamined 6 years later to observe changes in height, weight, blood pressure, lipids and lipoproteins between adolescence and adulthood. During the 6 years of follow-up, 10-11 year-old males increased 30 cm in height and 32 kg in weight. Among 10-11 year-old girls, height increased 12-15 cm and weight increased 15 kg in whites and 20 kg in blacks. Mean systolic BP increased 16-23 mmHg in black males and 11-15 mmHg in white males. Mean serum total cholesterol levels increased with age such that levels in 20 year olds were 160-190 mg/dl, about 10 to 15 mg/dl higher than 18 year olds. In white males beta-lipoprotein cholesterol increased (13 mg/dl) with age; however, there was a simultaneous decrease in alpha-lipoprotein cholesterol (11 mg/dl), resulting in a dramatic rise in the beta-LPC/alpha-LPC ratio. These adverse changes in LPC may be related to the early development of atherosclerosis and risk for coronary heart disease of young white men. Early identification of hypertension and hyperlipoproteinemia should help to predict and prevent future CV disease.
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PMID:Transitions of cardiovascular risk from adolescence to young adulthood--the Bogalusa Heart Study: II. Alterations in anthropometric blood pressure and serum lipoprotein variables. 394 31

Lysolecithin (LPC) induced a rapid but transitory increase in 45Ca2+ influx, and an abrupt 45Ca2+ net uptake by pigeon red cells. The effect on uptake was seen with doses of added lysolecithin calculated to be 2.1-8.4% of the cytoplasmic membrane phospholipid, well within the reported physiological range of 1-9%. Lysolecithin effects were not due to prelytic membrane changes nor action as a platelet activating factor agonist. Changes in the amino acids in the medium mimicking human homocysteinuria, an atherosclerosis risk factor, increased the lysolecithin effect. The findings are consistent with a role for lysolecithin in atherosclerosis.
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PMID:Lysolecithin-induced Ca2+ uptake by pigeon red cells. 395 21

Children initially aged 21/2 to 14 years living in Bogalusa, Louisiana (n = 2530) were examined twice, 3 years apart, for fasting serum pre-beta- and beta-lipoprotein cholesterol (beta-LPC) levels. Based on averages of these levels, the children were ranked for pre-beta- and beta-LPC in combinations of extreme quintiles (low-low, high-high) or quartiles (low-high, high-low), n = 388, and were reexamined for serum lipids, lipoprotein cholesterol, glucose tolerance, and anthropometry. Skinfolds were thicker in whites than in blacks except for subscapular skinfold. Children in the high-high stratum were heavier and more obese. The postglucose insulin level was positively correlated with fasting serum triglycerides and pre-beta-LPC. Compared with other strata, high-high strata showed more clustering among half-hour and 1-hour plasma insulin, serum triglycerides and pre-beta-LPC, and trunk skinfolds. We conclude that racial differences in lipid and carbohydrate metabolism occur in all four strata, and that a strong clustering occurs more in the high-high stratum, which may, in part, explain the coincidence of several high cardiovascular risk factor levels observed in the same children. These observations document in free-living children changes of obesity, plasma glucose, and insulin metabolism related to serum lipoproteins that are involved in the early natural history of atherosclerosis.
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PMID:Clustering of anthropometric parameters, glucose tolerance, and serum lipids in children with high and low beta- and pre-beta-lipoproteins. Bogalusa Heart Study. 705 36

Human serum paraoxonase (PON1) can protect low density lipoprotein (LDL) from oxidation induced by either copper ion or by the free radical generator azo bis amidinopropane hydrochloride (AAPH). During LDL oxidation in both of these systems, a time-dependent inactivation of PON arylesterase activity was observed. Oxidized LDL (Ox-LDL) produced by lipoprotein incubation with either copper ion or with AAPH, indeed inactivated PON arylesterase activity by up to 47% or 58%, respectively. Three possible mechanisms for PON inactivation during LDL oxidation were considered and investigated: copper ion binding to PON, free radical attack on PON, and/or the effect of lipoprotein-associated peroxides on the enzyme. As both residual copper ion and AAPH are present in the Ox-LDL preparations and could independently inactivate the enzyme, the effect of minimally oxidized (Ox-LDL produced by LDL storage in the air) on PON activity was also examined. Oxidized LDL, as well as oxidized palmitoyl arachidonoyl phosphatidylcholine (PAPC), lysophosphatidylcholine (LPC, which is produced during LDL oxidation by phospholipase A2-like activity), and oxidized cholesteryl arachidonate (Ox-CA), were all potent inactivators of PON arylesterase activity (PON activity was inhibited by 35%-61%). PON treatment with Ox-LDL (but not with native LDL), or with oxidized lipids, inhibited its arylesterase activity and also reduced the ability of the enzyme to protect LDL against oxidation. PON Arylesterase activity however was not inhibited when PON was pretreated with the sulfhydryl blocking agent, p-hydroxymercurybenzoate (PHMB). Similarly, on using recombinant PON in which the enzyme's only free sulfhydryl group at the position of cysteine-284 was mutated, no inactivation of the enzyme arylesterase activity by Ox-LDL could be shown. These results suggest that Ox-LDL inactivation of PON involves the interaction of oxidized lipids in Ox-LDL with the PON's free sulfhydryl group. Antioxidants such as the flavonoids glabridin or quercetin, when present during LDL oxidation in the presence of PON, reduced the amount of lipoprotein-associated lipid peroxides and preserved PON activities, including its ability to hydrolyze Ox-LDL cholesteryl linoleate hydroperoxides. We conclude that PON's ability to protect LDL against oxidation is accompanied by inactivation of the enzyme. PON inactivation results from an interaction between the enzyme free sulfhydryl group and oxidized lipids such as oxidized phospholipids, oxidized cholesteryl ester or lysophosphatidylcholine, which are formed during LDL oxidation. The action of antioxidants and PON on LDL during its oxidation can be of special benefit against atherosclerosis since these agents reduce the accumulation of Ox-LDL by a dual effect: i.e. prevention of its formation, and removal of Ox-LDL associated oxidized lipids which are generated during LDL oxidation.
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PMID:Human serum paraoxonase (PON 1) is inactivated by oxidized low density lipoprotein and preserved by antioxidants. 1023 33

Oxidized low-density lipoprotein (oxLDL) consists of both lipid components and apoprotein B100. OxLDL has both proinflammatory and cytotoxic properties. The present study was undertaken to investigate the effects of components in the lipid moiety of oxLDL on immune activation as determined by cytokine and immunoglobulin secretion. LPC induced interferon-gamma (IFN-gamma) secretion in peripheral blood mononuclear leucocytes from healthy blood donors. The effect varied between individuals, and there were both responders and non-responders. Furthermore, LPC induced enhanced antibody production, indicating B cell activation. None of eight oxysterols, arachidonic acid (AA), or 15-lipoxygenase products of AA tested had immune stimulatory properties. We recently demonstrated that PAF and oxLDL induce IFN-gamma secretion by a common mechanism. LPC-induced IFN-gamma secretion was inhibited by a specific PAF receptor antagonist, WEB 2170, indicating that the PAF receptor is involved in LPC-induced immune activation. Both oxLDL- and LPC-induced antibody formation was inhibited by WEB 2170. Furthermore LPC also induced tumour necrosis factor-alpha secretion, and this effect was inhibited by WEB 2170. LPC is produced during lipid oxidation (as in oxLDL), but also by enzymes such as phospholipase A2. The findings indicate that LPC may play an important role in inflammatory reactions, including atherosclerosis.
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PMID:Lysophosphatidylcholine (LPC) induces proinflammatory cytokines by a platelet-activating factor (PAF) receptor-dependent mechanism. 1033 26

Lysophospholipids, particularly lysophosphatidylcholine (lyso-PC), have been implicated in modulating T cell functions at the sites of inflammation and atherosclerosis. Although the chemotactic and immunomodulatory effects are well documented, the exact signaling pathway of lyso-PC action is poorly defined. In this work, we studied the earliest biochemical events in T cells triggered by lyso-PC. A marked and immediate tyrosine phosphorylation was induced in the leukemic T cell line, Jurkat. Phosphorylation of cellular substrates included src family kinase, p56(lck) and syk family kinase, ZAP70. The lyso-PC induced tyrosine phosphorylation was largely dependent on the presence of functional p56(lck). Tyrosine phosphorylation was followed by the elevation of intracellular Ca(2+) concentration. The magnitude of the mobilization of the intracellular Ca(2+) was similar in the absence of the p56(lck) activity in JCaM1.6 cells as in Jurkat cells, however, it was slightly but reproducibly delayed compared to that in the wild type cells. Inhibition of the Ser/Thr kinases and tyrosine kinases with staurosporine and genistein, respectively, decreased the rise in the intracellular Ca(2+) content. Moreover, pertussis toxin completely blocked the Ca(2+) signal supporting the role of the G-protein coupled LPC receptor in this event.
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PMID:Lysophosphatidylcholine is a regulator of tyrosine kinase activity and intracellular Ca(2+) level in Jurkat T cell line. 1475 65

The oxidation of plasma LDLs (low-density lipoproteins) is a key event in the pathogenesis of atherosclerosis. LPC (lysophosphatidylcholine) and oxysterols are major lipid constitutents of oxidized LDLs. In particular, 7-oxocholesterol has been found in plasma from cardiac patients and atherosclerotic plaque. In the present study, we investigated the ability of 7-oxocholesterol and LPC to regulate the activation of eNOS (endothelial nitric oxide synthase) and cPLA2 (cytosolic phospholipase A2) that synthesize two essential factors for vascular wall integrity, NO (nitric oxide) and arachidonic acid. In endothelial cells from human umbilical vein cords, both 7-oxocholesterol (150 microM) and LPC (20 microM) decreased histamine-induced NO release, but not the release activated by thapsigargin. The two lipids decreased NO release through a PI3K (phosphoinositide 3-kinase)-dependent pathway, and decreased eNOS phosphorylation. Their mechanisms of action were, however, different. The NO release reduction was dependent on superoxide anions in LPC-treated cells and not in 7-oxocholesterol-treated ones. The Ca2+ signals induced by histamine were abolished by LPC, but not by 7-oxocholesterol. The oxysterol also inhibited (i) the histamine- and thapsigargin-induced arachidonic acid release, and (ii) the phosphorylation of both cPLA2 and ERK1/2 (extracellular-signal-regulated kinases 1/2). The results show that 7-oxocholesterol inhibits eNOS and cPLA2 activation by altering a Ca2+-independent upstream step of PI3K and ERK1/2 cascades, whereas LPC desensitizes eNOS by interfering with receptor-activated signalling pathways. This suggests that 7-oxocholesterol and LPC generate signals which cross-talk with heterologous receptors, effects which could appear at early stage of atherosclerosis.
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PMID:Lysophosphatidylcholine and 7-oxocholesterol modulate Ca2+ signals and inhibit the phosphorylation of endothelial NO synthase and cytosolic phospholipase A2. 1499 85

Paraoxonases PON1 and PON3, which are both associated in serum with HDL, protect the serum lipids from oxidation, probably as a result of their ability to hydrolyze specific oxidized lipids. The activity of HDL-associated PON1 seems to involve an activity (phospholipase A2-like activity, peroxidase-like activity, lactonase activity) which produces LPC. To study the possible role of PON1 in macrophage foam cell formation and atherogenesis we used macrophages from control mice, from PON1 knockout mice, and from PON1 transgenic mice. Furthermore, we analyzed PON1-treated macrophages and PON1-transfected cells to demonstrate the contribution of PON1 to the attenuation of macrophage cholesterol and oxidized lipid accumulation and foam cell formation. PON1 was shown to inhibit cholesterol influx [by reducing the formation of oxidized LDL (Ox-LDL), increasing the breakdown of specific oxidized lipids in Ox-LDL, and decreasing macrophage uptake of Ox-LDL]. PON1 also inhibits cholesterol biosynthesis and stimulates HDL-mediated cholesterol efflux from macrophages. PON2 and PON3 protect against oxidative stress, with PON2 acting mainly at the cellular level. Whereas serum PON1 and PON3 were inactivated under oxidative stress, macrophage PON2 expression and activity were increased under oxidative stress, probably as a compensatory mechanism against oxidative stress. Intervention to increase the paraoxonases (cellular and humoral) by dietary or pharmacological means can reduce macrophage foam cell formation and attenuate atherosclerosis development.
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PMID:Paraoxonases 1, 2, and 3, oxidative stress, and macrophage foam cell formation during atherosclerosis development. 1545 71


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