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)

Atherosclerosis is a multifactorial disease, where more than one mechanism, along more than one step, contributes to macrophage cholesterol accumulation and foam cell formation, the hallmark of early atherogenesis. Arterial macrophages take up oxidized low-density lipoproteins (Ox-LDL), leading to cellular accumulation of cholesterol and oxysterols. Atherogenic modifications of LDL include, in addition to oxidation, retention and aggregation. Intervention to inhibit LDL oxidation can affect the above additional LDL modifications. Indeed, we have demonstrated in the atherosclerotic apolipoprotein E-deficient mice that consumption of vitamin E or of flavonoids from red wine or licorice decreased LDL oxidation, LDL retention, and LDL aggregation and attenuated macrophage foam cell formation and atherosclerosis. The balance between pro-oxidants and anti-oxidants in the LDL particle (such as cholesteryl ester vs. vitamin E), as well as in arterial wall macrophages (such as NADPH oxidase vs. glutathione), determines the extent of LDL oxidation. Antioxidants can protect LDL from oxidation not only by their binding to the lipoprotein, but also following their accumulation in cells of the arterial wall. Whereas antioxidants can prevent the formation of Ox-LDL, human serum paraoxonase (PON 1), an HDL-associated esterase that hydrolyzes organophosphates, can eliminate oxidized LDL (by hydrolysis of its lipid peroxides), which is formed when antioxidant protection is not sufficient. Ox-LDL, in turn, can inactivate paraoxonase activity. Thus, the combination of antioxidants together with active paraoxonase decreases the formation of Ox-LDL and preserves PON1's ability to hydrolyze this atherogenic lipoprotein and hence, to attenuate atherosclerosis.
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PMID:Macrophage foam cell formation during early atherogenesis is determined by the balance between pro-oxidants and anti-oxidants in arterial cells and blood lipoproteins. 1123 55

Cardiac death from atherosclerosis is common in hemodialysis patients. Human serum paraoxonase (PON1), an esterase, is associated with high-density lipoprotein and inhibits the susceptibility to oxidization of low-density lipoprotein (LDL). The PON1 genetic polymorphisms of 192 Gln/Arg and 55 Leu/Met in the amino acid sequence are partly involved in the PON1 enzyme activity. We investigated the PON1 enzyme activities for paraoxon (paraoxonase) and phenylacetate (arylesterase), and the two polymorphisms in 96 patients undergoing hemodialysis and in 136 normal controls. Both activities were significantly lower in the hemodialysis patients than in the controls (97+/-43 vs 155+/-57 micromol/min/l for paraoxonase, and 71+/-20 vs 92+/-22 mmol/min/l for arylesterase, respectively). There was no difference in the distribution of the two polymorphisms between patients and controls, and in every subgroup classified by the polymorphisms, both paraoxonase and arylesterase activities were lower in patients than in controls. This suggested that the enzyme activities of PON1 decreased in hemodialysis patients, independent of the genetic polymorphism. The decrease in PON1 enzyme activity in hemodialysis patients may modify a susceptibility to oxidization of LDL, which contributes to an acceleration of atherosclerosis.
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PMID:Serum paraoxonase and arylesterase activities in hemodialysis patients. 1148 Apr 56

Human paraoxonase (PON1) is a calcium-dependent esterase exclusively bound to apolipoprotein A-I and clusterin, containing high-density lipoprotein (HDL) particles that hydrolyzes organophosphates and aryl esters. Several studies have indicated that PON1 can prevent low-density lipoprotein (LDL) oxidation by hydrolyzing lipid peroxides in the lipoprotein, which is the crucial first step for atherogenesis. Therefore it may protect against the development of atherosclerosis. Serum PON1 activity has been shown to be decreased in familiar hypercholesterolemia and in diseases that are associated with accelerated atherogenesis. The PON1 gene has two common coding region polymorphisms, Leu55-->Met and Gln192-->Arg. Both polymorphisms have been identified as independent risk factors for cardiovascular disease in diabetic and non-diabetic patients. We have established high-speed and easy-to-perform genotyping for the two most significant PON1 gene polymorphisms, employing the LightCycler technology and melting curves. This technique eliminates PCR contamination related to sample handling and does not require digestion of PCR products with restriction enzymes and/or fragment separation on gels.
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PMID:High-speed detection of the two common paraoxonase polymorphisms Leu55-->Met and Gln192-->Arg by real-time fluorescence PCR and melting curves. 1205 71

Human serum paraoxonase (PON1), an HDL-associated esterase, protects lipoproteins against oxidation, probably by hydrolyzing specific lipid peroxides. As arterial macrophages play a key role in oxidative stress in early atherogenesis, the aim of the present study was to examine the effect of PON1 on macrophage oxidative stress. For this purpose we used mouse arterial and peritoneal macrophages (MPM) that were harvested from two populations of PON1 knockout (KO) mice: one on the genetic background of C57BL/6J (PON1(0)) and the other one on the genetic background of apolipoproteinE KO (PON1(0)/E(0)). Serum and LDL, but not HDL, lipids peroxidation was increased in PON1(0), compared to C57BL/6J mice, by 84% and by 220%, respectively. Increased oxidative stress was shown in peritoneal and in arterial macrophages derived from either PON1(0) or PON1(0)/E(0) mice, compared to their appropriate controls. Macrophage oxidative stress was expressed by increased lipid peroxides content in MPM from PON1(0) and from PON1(0)/E(0) mice by 48% and by 80%, respectively, and by decreased reduced glutathione (GSH) content, compared to the appropriate controls. Furthermore, increased capacity of MPM from PON1(0) and PON1(0)/E(0) mice to oxidize LDL (by 40% and by 19%, respectively) and to release superoxide anions was observed. In accordance with these results, PON1(0) mice MPM exhibited 130% increased translocation of the cytosolic p47phox component of NADPH-oxidase to the macrophage plasma membrane, suggesting increased activation of macrophage NADPH-oxidase in PON1(0) mice, compared to control mice MPM. The increase in oxidative stress in PON1-deficient mice was observed despite the presence of the two other members of the PON gene family. PON2 and PON3 activities and mRNA expression were both found to be present in PON1-deficient mice MPM. Upon incubation of PON1(0)/E(0) derived macrophages with human PON1 (7.5 arylesterase units/ml), cellular peroxides content was decreased by 18%, macrophage superoxide anion release was decreased by 33%, and macrophage-mediated oxidation of LDL was reduced by 22%. Finally, a 42% increase in the atherosclerotic lesion area was observed in PON1(0)/E(0) mice, in comparison to E(0) mice under regular chow diet. We thus concluded that PON1 can directly reduce oxidative stress in macrophages and in serum, and that PON1-deficiency results in increased oxidative stress not only in serum, but also in macrophages, a phenomenon that can contribute to the accelerated atherosclerosis shown in PON1-deficient mice.
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PMID:Paraoxonase (PON1) deficiency is associated with increased macrophage oxidative stress: studies in PON1-knockout mice. 1263 54

The human paraoxonase (PON) gene family consists of three members, PON1, PON2, and PON3, aligned next to each other on chromosome 7. By far the most-studied member of the family is the serum paraoxonase 1 (PON1), a high-density lipoprotein-associated esterase/lactonase. Early research focused on its capability to hydrolyze toxic organophosphates, and its name derives from one of its most commonly used in vitro substrates, paraoxon. Studies in the last 2 decades have demonstrated PON1's ability to protect against atherosclerosis by hydrolyzing specific derivatives of oxidized cholesterol and/or phospholipids in oxidized low-density lipoprotein and in atherosclerotic lesions. Levels and genetic variability of PON1 influence sensitivity to specific insecticides and nerve agents, as well as the risk of cardiovascular disease. More recently, the other two members of the PON family, PON2 and PON3, have also been shown to have antioxidant properties. A major goal in present research on the paraoxonases is to identify their natural substrates and to elucidate the mechanism(s) of their catalytic activities.
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PMID:Pharmacogenetics of paraoxonases: a brief review. 1457 13

Acetylcholine esterase (AChE) and paraoxonase 1 (PON1) are both serum ester hydrolases, which are associated with the prevalence of myocardial infarction. Both genes are located in close proximity on chromosome 7q21-22. As PON1 was suggested to protect against cardiovascular diseases secondary to its ability to break down oxidized lipids and to inhibit LDL oxidation, we examined AChE capacity to protect LDL against oxidation. Preincubation of LDL with AChE retarded the onset of copper ion-induced LDL oxidation in a concentration-dependent manner. AChE significantly reduced the formation of lipid peroxides and TBARS during the course of LDL oxidation, by up to 45%. This effect was associated with AChE-mediated hydrolysis of lipid peroxides, which accounts for the inhibition in the onset of LDL oxidation, the oxidative propagation phase, and aldehyde formation. We conclude that AChE, similar to PON1, can hydrolyze lipid peroxides and thus may prevent the accumulation of oxidized LDL and attenuate atherosclerosis development.
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PMID:Acetylcholine esterase protects LDL against oxidation. 1533 59

Serum paraoxonase (PON1) is a high-density lipoprotein (HDL)-associated esterase/lactonase implicated to play a role in protection against atherosclerosis. However, the exact mechanism(s) and substrates for PON1 are still uncertain. In this article, we review some of the evidence for PON1's antioxidant activity, as well as our efforts to identify the actual substrates and products for this activity. We originally reported that PON1 had phospholipase activity toward oxidized phosphatidylcholine (J. Biol. Chem. 276:24473-24481; 2001). Subsequently, Marathe et al. (J. Biol. Chem. 278:3937-3947; 2003) reported that this activity was due to a contaminating lipase. However, that article did not replicate the conditions used in our previous study. To address this controversy, we purified serum PON1 by a modified method that separates the paraoxonase activity from an activity detectable as platelet-activating factor acetyl hydrolase (PAF-AH) (Teiber et al., J. Lipid. Res. 2004; Epub ahead of print, PMID 15342686) and reexamined the oxidation of phosphatidylcholine by peroxynitrite using 3-morpholinosydnonimine as a peroxynitrite generator and apolipoprotein AI-phosphatidylcholine- PON1 complexes. The phosphatidylcholines were studied by electrospray ionization tandem mass spectrometry. PON1 preparations free of PAF-AH activity showed no phospholipase activity when reconstituted into apolipoprotein AI-phosphatidylcholine complexes. We conclude that PON1 does not affect the accumulation of phosphatidylcholine oxidation products. Further, we have no evidence that PON1 has an intrinsic phospholipase A2 activity toward oxidized phospholipids.
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PMID:Paraoxonase-1 does not reduce or modify oxidation of phospholipids by peroxynitrite. 1560

Paraoxonase 1 (PON1) is an esterase, associated in serum with high density lipoprotein (HDL). As diet affects serum PON1 activity, we questioned whether PON1 is also carried by postprandial chylomicrons. Chylomicrons were isolated by ultracentrifugation from plasma of 10 healthy men, 3h after the consumption of a high fat, high carbohydrate meal, and were analyzed for the presence of PON1 arylesterase activity and protein. The present study shows for the first time that, in addition to the presence of PON1 mainly on HDL, postprandial chylomicrons also contain minor, but significant amount of PON1. PON1 was also present in chylomicrons derived from fasted patients with hyperchylomicronemia. In addition, PON1 was detected in very low density lipoprotein (VLDL), but not in LDL. The origin of chylomicron PON1 could be partly attributed to its transfer from HDL. Finally, this study demonstrates that postprandial chylomicrons inhibit copper ion-induced LDL oxidation, secondary to hydrolysis of lipid peroxides, a phenomenon which could be related, at least in part, to the chylomicron PON1 content. We conclude that postprandial chylomicrons contain PON1, which may function in the removal of atherogenic oxidized lipids.
Atherosclerosis 2005 May
PMID:Paraoxonase 1 (PON1) is present in postprandial chylomicrons. 1582 75

Carotid intima media thickness (IMT), represents an important clinical indicator of early atherosclerosis. Human plasma platelet-activating factor acetylhydrolase (PAF-AH) is an enzyme primarily associated with low-density lipoprotein (LDL) while a small proportion of enzymatic activity is also associated with high-density lipoprotein (HDL). Plasma paraoxonase 1 (PON1) is an esterase exclusively associated with HDL. The authors investigated the possible relationship between carotid IMT and the plasma levels of PAF-AH mass and activity as well as the PON1 activity in hyperlipidemic patients. One hundred unrelated patients with primary hyperlipidemia and 67 age-and sex-matched normolipidemic apparently healthy volunteers participated in the study. The PAF-AH activity in total plasma and in HDL-rich plasma (HDL-PAF-AH activity), the plasma PAF-AH mass, and the serum PON1 activities toward paraoxon and phenyl acetate were determined. The plasma PAF-AH mass and activity were higher in hyperlipidemic patients compared to controls, whereas the HDL-PAF-AH activity, as well as the serum PON1 activities were not significantly different between the studied groups. When hyperlipidemic patients were divided into 2 subgroups according to their IMT values (IMT <0.7 mm and IMT > or =0.7 mm) patients with IMT > or =0.7 mm had significantly higher age, and serum triglyceride concentrations, whereas no difference was found in the plasma PAF-AH mass and activity as well as in the HDL-PAF-AH activity between the 2 studied subgroups. The same phenomenon was observed for serum PON1 activities. In a multivariate analysis, only the age was significantly correlated with IMT values (p<0.05). Neither the total plasma PAF-AH mass and activity nor the HDL-PAF-AH activity are associated with early carotid atherosclerosis.
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PMID:Lack of association between carotid intima-media thickness and PAF-acetylhydrolase mass and activity in patients with primary hyperlipidemia. 1607 29

An increased concentration of homocysteine is an important risk factor of atherosclerosis; however, the mechanism of the proatherogenic effect of this amino acid is not yet known. Studies performed during the last two decades suggest that the atherogenic effect of homocysteine may be accounted for by homocysteine thiolactone (HCTL). Homocysteine is nonspecifically activated by methionyl-tRNA synthetase; however, it is not transferred to tRNA and incorporated into proteins, but is transformed to a cyclic thioester, homocysteine thiolactone. HCTL is highly reactive and acylates free amino groups of protein lysine residues, the process referred to as protein N-homocysteinylation. Various plasma proteins are homocysteinylated in vitro and in vivo. Homocysteinylation results in the incorporation of additional thiol groups which may alter the physicochemical properties and biological activity of proteins. In particular, homocysteinylation of low-density lipoproteins (LDLs) increases their susceptibility to oxidation and accelerates their uptake by macrophages. In addition, homocysteinylated LDL elicit humoral immune response. Anti-homocysteinyllysine antibodies are detected in plasma of healthy humans and their titer is elevated in patients with ischemic heart disease or ischemic cerebral stroke. Homocysteine thiolactone is hydrolyzed to homocysteine by paraoxonase (PON), a calcium-dependent esterase synthesized in the liver and contained in plasma high-density lipoproteins (HDLs). Protein homocysteinylation may contribute to accelerated atherogenesis in individuals with hyperhomocysteinemia.
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PMID:Protein homocysteinylation: a new mechanism of atherogenesis? 1610 41


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