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)

Arylesterase activity (EC 3.1.1.2), one of the three functions of the paraoxonase enzyme (PON1), is thought to protect low-density lipoproteins (LDL) and high-density lipoprotein (HDL) from oxidation and to facilitate reverse cholesterol transport. The Eckerson et al. method, which employs Tris/HCl buffer, has been extensively used and could be considered as the reference method, although it shows relatively low precision and reproducibility. Using simulated body fluid (SBF), which simulates blood electrolyte composition, a significant improvement in arylesterase activity determination was achieved. Modifications of SBF bicarbonate and chloride concentrations did not result in further improvements. To validate this method arylesterase activity was measured using SBF and Tris/HCl in 23 subjects with increased cardiovascular disease risk. Precision was significantly higher using SBF than with Tris/HCl. Data from both methods do not significantly differ in samples with arylesterase activity > or = 30.6 U/L using SBF, but do differ significantly when very low activity samples (< 30.6 U/L) were included. Differences suggest that the Tris/HCl buffer gives misleading activity results, especially in very low activity samples. For the first time, results suggest that SBF can successfully be used instead of Tris/HCl in arylesterase activity determination.
Atherosclerosis 2006 Sep
PMID:A new method for the determination of arylesterase activity in human serum using simulated body fluid. 1629 89

Human serum paraoxonase 1 (hPON1) belongs to a family of enzymes that catalyze the hydrolysis of a broad range of esters and lactones. Although the very first identification of hPON1 might have been as a calcium-dependent paraoxonase/arylesterase, PON1 is in fact a lactonase associated with high-density lipoprotein and strongly stimulated by apoA-I. PON1 hydrolyzes various organophosphates, including insecticides and nerve gases. PON1 also plays a key role in prevention of atherosclerosis. Mediation of cholesterol efflux from macrophage is a key in vivo function of PON1. In present study, the hPON1 Q gene was cloned into baculovirus transfer vector pVL1392 and expressed in silkworm expression system. The rhPON1 Q presented two bands with every near molecular weight of about 40 and 43 kDa according to sodium dodecyl sulphate-polyacrylamide gel electrophoresis and Western blotting analysis. The expression level was up to 1,256 mg/L in haemolymph, about 50 times as high as that from BmN cells (24.8 mg/L). After purified by two chromatography steps (DEAE-Sepharose and HiTrap Chelating HP), the purity of rhPON1 Q was up to 90%, and the enzymatic properties are similar to serum hPON1.
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PMID:High-level expression of recombinant human paraoxonase 1 Q in silkworm larvae (Bombyx mori). 1633 52

Paraoxonase (PON1) is a liver and plasma enzyme most studied because of its ability to hydrolyze the active metabolites of several organophosphorus insecticides. The discovery that PON1 can also metabolize oxidized phospholipids has spurred research on its possible role in coronary heart disease and atherosclerosis. Additionally, its potential roles in metabolizing pharmaceutical drugs and microbial quorum sensing factors are also being explored. PON1 displays several polymorphisms that influence both its level of expression and its catalytic activity, thus determining the rates at which a given individual will detoxify a specific insecticide, metabolize harmful oxidized lipids, and activate or inactivate specific drugs and quorum sensing factors.
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PMID:Paraoxonase (PON1): from toxicology to cardiovascular medicine. 1635 44

Human phosphate-binding protein (HPBP) was serendipitously discovered by crystallization and X-ray crystallography. HPBP belongs to a eukaryotic protein family named DING that is systematically absent from the genomic database. This apoprotein of 38 kDa copurifies with the HDL-associated apoprotein paraoxonase (PON1) and binds inorganic phosphate. HPBP is the first identified transporter capable of binding phosphate ions in human plasma. Thus, it may be regarded as a predictor of phosphate-related diseases such as atherosclerosis. In addition, HPBP may be a potential therapeutic protein for the treatment of such diseases. Here, the purification, detergent-exchange protocol and crystallization conditions that led to the discovery of HPBP are reported.
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PMID:Crystallization and preliminary X-ray diffraction analysis of human phosphate-binding protein. 1651 Dec 65

The aim of this study was to determine whether the paraoxonase (PON1) status, i.e. PON1 activities and phenotypes (AA, AB and BB), and its relationship with lipid status are different in patients with type II diabetes as compared to healthy population. Diabetic group comprised 175 patients with type II diabetes mellitus (94 men and 81 women) who came to their regular control examination and took the oral glucose tolerance test. Patients with type II diabetes mellitus diagnosis for 12 years on average were on peroral antidiabetics, or insulin or diet, and 3 patients had no therapy prescribed yet. Control group comprised 114 apparently healthy individuals (28 men and 86 women) who were not on any medication. The paraoxonase activity was measured with 2.0 mmol L(-1) paraoxon in the absence and in the presence of 1.0 mol L(-1) NaCl, and with 2.0 mmol L(-1) phenylacetate. Both activities were measured spectrophotometrically at 37 degrees C in 0.1 mol L(-1) Tris-HCl buffer, pH = 8.0, containing 2.0 mmol L(-1) CaCl(2). Sera of diabetic and control subjects were assigned to the paraoxonase phenotypes on the basis of the basal paraoxonase activity distribution. We assigned 45% sera of male and 49% sera of female diabetic patients, and 64% sera of both genders of the control group to the AA low activity phenotype. There were no differences in paraoxonase activities between the gender- and phenotype-matched diabetic and control groups. Enzyme activity against the phenylacetate was higher, and phenotype-dependent, only in diabetic patients. In contrast to AA phenotype individuals, total cholesterol and LDL-cholesterol in the female diabetic group and triglyceride concentration in the male diabetic group assigned to pooled AB and BB phenotypes were higher than in the corresponding controls. It follows from PON1 phenotype distribution that less antiatherogenic paraoxonase B allele is more frequent in type II diabetes mellitus than in the healthy population. Their lipid status is more atherogenic, which could indicate a risk of premature atherosclerosis.
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PMID:Paraoxonase/arylesterase in serum of patients with type II diabetes mellitus. 1661 35

It was reported that lipid peroxidation (LPO) products increase in rheumatoid arthritis (RA) patients and increased LPO products reduce many antioxidants. Lipid hydroperoxides (LOOHs) are byproduct of LPO. Paraoxonase (PON), arylesterase (ARE), free sulfhydryl (SH) groups, and ceruloplasmin (CP) are enzymes or proteins with antioxidant characteristics. This study aims to determine the levels of LOOHs and SH, and the activities of PON1, ARE, and CP in RA patients. The study included 47 active RA cases and 23 healthy volunteers. The levels of LOOHs and SH, and the activities of PON1, ARE, and CP were determined using appropriate methods. Student's t test and Spearman's correlation analysis methods were employed in the statistical evaluation. The level of LOOHs was found to be higher (p<0.001), while the level of SH and the activities of PON1, ARE, and CP were found to be lower (p<0.001, <0.001, <0.01, and <0.01, respectively) in the RA patient group when compared with the control group. There was a negative correlation between the level of LOOHs and the activity of PON1 in the patient group (r= -0.420 and p<0.01). The results of our study indicate increased oxidant and decreased antioxidant presence in RA patients. PON1 and ARE are known to have antiatherosclerotic effects in addition to their antioxidant characteristics. As the decrease in these antioxidants, resulting from increased oxidative stress in RA patients, development of atherosclerosis besides tissue injury seems inevitable.
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PMID:Paraoxonase and arylesterase levels in rheumatoid arthritis. 1664 6

Highly active antiretroviral therapy in Human Immunodeficiency Virus (HIV) has been associated with lipodystrophy, insulin resistance and atherosclerosis. We investigated the effects of rosiglitazone or metformin on fasting and postprandial inflammatory and antioxidant variables in HIV-infected males with lipodystrophy. Thirty-one patients were randomly assigned to receive either rosiglitazone (4 mg twice daily) or metformin (1 g twice daily) for 26 weeks. At baseline and after treatment, standardized 10-h oral fat loading tests were performed. Before treatment, inflammatory variables remained unchanged but there was a postprandial decrease in high density lipoprotein (HDL)-cholesterol and paraoxonase (PON1) activity. Rosiglitazone and metformin reduced homeostasis model assessment index (HOMA) similarly (-34% and -37%, respectively, P<0.05 for each). Both treatments increased fasting and postprandial PON1 activity and decreased postprandial monocyte chemoattractant protein 1 (MCP-1) concentrations. However, plasma C-reactive protein (CRP) and Interleukin-6 (IL-6) concentration did not change throughout the study. To decrease insulin resistance results in a higher anti-oxidant and consequent lower pro-inflammatory action of HDL. This may confer protection against accelerated atherosclerosis in these patients.
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PMID:Effects of rosiglitazone and metformin on postprandial paraoxonase-1 and monocyte chemoattractant protein-1 in human immunodeficiency virus-infected patients with lipodystrophy. 1684 55

Paraoxonases (PONs) are a family of proteins that may play a significant role in providing relief from both toxic environmental chemicals as well as physiological oxidative stress. Although the physiological roles of the PON family of proteins, PON1, PON2, and PON3, remain unknown, epidemiological, biochemical, and mouse genetic studies of PON1 suggest an anti-atherogenic function for paraoxonases. To determine whether PON2 plays a role in the development of atherosclerosis in vivo, we generated PON2-deficient mice. When challenged with a high fat, high cholesterol diet for 15 weeks, serum levels of high density lipoprotein cholesterol, triglycerides, and glucose were not significantly different between wild-type and PON2-deficient mice. In contrast, serum levels of very low density lipoprotein (VLDL)/low density lipoprotein (LDL) cholesterol were significantly lower (-32%) in PON2-deficient mice compared with wild-type mice. However, despite lower levels of VLDL/LDL cholesterol, mice deficient in PON2 developed significantly larger (2.7-fold) atherosclerotic lesions compared with their wild-type counterparts. Enhanced inflammatory properties of LDL, attenuated anti-atherogenic capacity of high density lipoprotein, and a heightened state of oxidative stress coupled with an exacerbated inflammatory response from PON2-deficient macrophages appear to be the main mechanisms behind the larger atherosclerotic lesions in PON2-deficient mice. These results demonstrate that PON2 plays a protective role in atherosclerosis.
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PMID:Paraoxonase-2 deficiency aggravates atherosclerosis in mice despite lower apolipoprotein-B-containing lipoproteins: anti-atherogenic role for paraoxonase-2. 1689 3

Serum paraoxonase (PON1) is a HDL-associated enzyme exhibiting potentially antiatherogenic properties. Here, we examined the common PON1-192R/Q human polymorphism. Despite numerous studies, the effect of this polymorphism on the antiatherogenic potential of PON1 is yet unresolved. Our structural model suggests that amino acid 192 constitutes part of the HDL-anchoring surface and active site of PON1. Based on our findings that PON1 is an interfacially activated lipolactonase that selectively binds HDL carrying apolipoprotein A-I (apoA-I) and is thereby greatly stabilized and catalytically activated, we examined the interaction of the PON1-192 isozymes with reconstituted HDL-apoA-I particles. We found that PON1 position 192 is indeed involved in HDL binding. The PON1-192Q binds HDL with a 3-fold lower affinity than the R isozyme and consequently exhibits significantly reduced stability, lipolactonase activity, and macrophage cholesterol efflux. We also observed the lower affinity and stability of the 192Q versus the 192R isozyme in sera of individuals belonging to the corresponding genotypes. The observed differences in the properties of PON1-192R/Q isozymes provide a basis for further analysis of the contribution of the 192R/Q polymorphism to the susceptibility to atherosclerosis, although other factors, such as the overall levels of PON1, may play a more significant role.
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PMID:The 192R/Q polymorphs of serum paraoxonase PON1 differ in HDL binding, lipolactonase stimulation, and cholesterol efflux. 1691 70

Paraoxonase 3 (PON3) is a member of the PON family, which includes PON1, PON2, and PON3. Recently, PON3 was shown to prevent the oxidation of low-density lipoprotein in vitro. To test the role of PON3 in atherosclerosis and related traits, 2 independent lines of human PON3 transgenic (Tg) mice on the C57BL/6J (B6) background were constructed. Human PON3 mRNA was detected in various tissues, including liver, lung, kidney, brain, adipose, and aorta, of both lines of Tg mice. The human PON3 mRNA levels in the livers of PON3 Tg mice were 4- to 7-fold higher as compared with the endogenous mouse Pon3 mRNA levels. Human PON3 protein and activity were detected in the livers of Tg mice as well. No significant differences in plasma total, high-density lipoprotein, and very-low-density lipoprotein/low-density lipoprotein cholesterol and triglyceride and glucose levels were observed between the PON3 Tg and non-Tg mice. Interestingly, atherosclerotic lesion areas were significantly smaller in both lines of male PON3 Tg mice as compared with the male non-Tg littermates on B6 background fed an atherogenic diet. When bred onto the low-density lipoprotein receptor knockout mouse background, the male PON3 Tg mice also exhibited decreased atherosclerotic lesion areas and decreased expression of monocyte chemoattractant protein-1 in the aorta as compared with the male non-Tg littermates. In addition, decreased adiposity and lower circulating leptin levels were observed in both lines of male PON3 Tg mice as compared with the male non-Tg mice. In an F2 cross, adipose Pon3 mRNA levels inversely correlated with adiposity and related traits. Our study demonstrates that elevated PON3 expression significantly decreases atherosclerotic lesion formation and adiposity in male mice. PON3 may play an important role in protection against obesity and atherosclerosis.
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PMID:Decreased obesity and atherosclerosis in human paraoxonase 3 transgenic mice. 1746 24


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