Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0007222 (cardiovascular disease)
 65,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Age is associated with an enhanced low density lipoprotein (LDL) oxidation and atherosclerosis, thus, subjects over 80 years without cardiovascular disease provide a model to investigate the protective factors against atherosclerosis. Serum paraoxonase (PON1), an high density lipoprotein (HDL)-bound enzyme, prevents LDL oxidation. The aim of the present study was to evaluate the contribution of the PON1 promoter T(-107)C and coding region Gln192Arg (Q192R) and Leu55Met (L55M) polymorphisms to the resistance to develop cardiovascular events in Sicilian healthy octogenarians. Distribution of PON1 genotypes and activity, and biochemical parameters, were compared between 100 octogenarians and 200 adults. Individuals in the elderly group displayed significant higher levels of HDL-C (P < 0.001) and PON1 activity (P < 0.001). The analysis of PON1 genotypes distribution showed an higher percentage of (-107)CC among octogenarians compared with controls. A significant difference among T(-107)C genotypes respect to PON1 activity and HDL-C levels occurred in both groups. The CC genotype was associated with higher PON1 activity and HDL levels compared to the TT genotypes. In conclusion, our results provide a strong evidence that in healthy Sicilians ageing may be characterized by a low frequency of PON1 (-107)T 'risk' allele and by an high frequency of favourable genotypes such as (-107)CC, influencing PON1 activity and HDL-C levels.
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PMID:Association between serum paraoxonase (PON1) gene promoter T(-107)C polymorphism, PON1 activity and HDL levels in healthy Sicilian octogenarians. 1523 68

The search for genes related to the cause of common complex disorders such as cardiovascular disease has been frustrating, partly because of the many factors known to contribute to cardiovascular disease and the potential "distance" of cardiovascular disease as a phenotype from genes and gene products. Linkage and association studies for phenotypes more proximal in the pathway from DNA sequence variation to overt clinical disease, such as ultrasound-defined carotid atherosclerosis, may potentially be more enlightening. Only one genetic variant previously reported to be associated with atherosclerosis or clinically evident cardiovascular disease, matrix metalloproteinase (MMP) 3, has shown consistently positive associations with carotid disease, although it has not been studied widely. Another, PON1 L55M, is weakly associated in subgroups only, and 2, ApoE and MTHFR, are equivocal. Genetic variants reported to be associated with clinical cardiovascular disease show weak or no relationship to carotid atherosclerosis. This may reflect the known inconsistency in associations of genetic variants with clinical cardiovascular disease itself. Alternatively, genetic determinants of ultrasound-defined carotid atherosclerosis may differ from those of clinically manifest cardiovascular disease and may require pursuit through large-scale genomic studies of carotid atherosclerosis as a distinct phenotype. Only 1 genetic variant, MMP 3, has shown consistently positive associations with ultrasonographic carotid disease, although it has not been studied widely. Another, PON1 L55 mol/L, is weakly associated in subgroups only. Genetic variants reported to be associated with clinical cardiovascular disease show weak or no relationship to carotid atherosclerosis.
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PMID:Genetics of ultrasonographic carotid atherosclerosis. 1552 87

The HDL-bound enzyme paraoxonase (PON) protects LDL from oxidation and may therefore attenuate the development of atherosclerosis. We examined the effect of tomato and carrot juice consumption on PON1 activity and lipid peroxidation in healthy young volunteers with different PON1-192 genotypes (Q/R substitution at position 192). In this randomized cross-over study twenty-two healthy, non-smoking men on a low-carotenoid diet received 330 ml/d tomato juice (37.0 mg lycopene, 1.6 mg beta-carotene) or carrot juice (27.1 mg beta-carotene, 13.1 mg alpha-carotene) for 2 weeks. Intervention periods were preceded by 2-week low-carotenoid intake. We determined the PON1-192 genotype by restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR) and measured ex vivo LDL oxidation (lag time), plasma malondialdehyde and PON1 activity at the beginning and end of each intervention period. At baseline, lag time was higher (P<0.05) in QQ (111 (sd 9) min) than in QR/RR subjects (101 (sd 8) min). Neither tomato nor carrot juice consumption had significant effects on PON1 activity. However, tomato juice consumption reduced (P<0.05) plasma malondialdehyde in QR/RR (Delta: -0.073 (sd 0.11) micromol/l) as compared to QQ subjects (Delta:+0.047 (sd 0.13) micromol/l). Carrot juice had no significant effect on malondialdehyde irrespective of the PON1-192 genotype. Male volunteers with the QR/RR genotype showed an increased lipid peroxidation at baseline. Although tomato and carrot juice fail to affect PON1 activity, tomato juice intake reduced lipid peroxidation in healthy volunteers carrying the R-allele of the PON1-192 genotype and could thus contribute to CVD risk reduction in these individuals.
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PMID:Paraoxonase 1 Q192R (PON1-192) polymorphism is associated with reduced lipid peroxidation in healthy young men on a low-carotenoid diet supplemented with tomato juice. 1587 67

Human serum paraoxonase (PON1) has been implicated to play an important role in cardiovascular disease and diabetes. Studies in the literature indicate that PON1 has two different enzyme activities, i.e., esterase and hydroperoxide reducing activities. The objective of this study was to establish the importance of these two activities and to distinguish between them. As the addition of copper immediately inactivated the enzyme, we used auto-oxidation as the model system. Auto-oxidation of HDL resulted in more than 80% reduction of the esterolytic activity, which was protected by antioxidants, Vitamin E (50%) and PDTC (95%) and completely by 1 M glucose. In contrast, the hydroperoxide reducing activity, using unesterified hydroperoxides remained unaffected with time. We also used pNPHPODE (novel substrate) to establish that hydrolysis might be a prerequisite for the enzyme to act on the esterified hydroperoxide. The results indicated that the hydrolysis of the substrate was inhibited under oxidizing conditions with no reduction of the hydroperoxide. Overall, our findings suggest that protecting the esterolytic activity of PON1 by antioxidants might be important in preserving its action on phospholipid peroxides and a concerted reaction involving the esterolytic and hydroperoxide reducing activities might be suggested for the action of PON1.
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PMID:Oxidative inactivation of paraoxonase--implications in diabetes mellitus and atherosclerosis. 1611 60

To identify all putative functional polymorphisms of PON gene cluster in Chinese Han population. Common polymorphisms of PON1, PON2 and PON3 gene were identified by directly sequencing of genomic DNAs derived from 48 randomly selected patients with coronary heart disease. We designed PCR arrays to amplify regions up to about 1kb upstream from transcription-initiation sites, i.e., putative promoter regions, all exons and adjacent non-coding regions. In a total length of 13.9 kb explored, we identified thirty-one SNPs, of which, 17 were first reported. A new coding polymorphism was detected in PON1 gene, which gives rise to amino acid substitutions of arginine (R) for glycine (G) at codon 160, whereas L54M polymorphism, which is common in white population, was not detected in our Han population. Among the five polymorphisms identified in PON3 gene, one in the promoter regions at position -133 (C/A) was located in a potential binding site for transcription factor LF-A1. Allele frequencies of some polymorphisms are significantly different from those reported in Caucasian populations. Complete or nearly complete association between polymorphisms was frequently observed. The identified multiple putative functional polymorphisms in PON gene cluster and their linkage disequilibrium patterns in combination with the population specific frequencies are of values for futher association studies of PON gene cluster with cardiovascular disease.
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PMID:[Polymorphisms screening of PON gene cluster]. 1612 May 73

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.
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PMID:A new method for the determination of arylesterase activity in human serum using simulated body fluid. 1629 89

Since the discovery of human serum paraoxonase (PON1), the enzyme has been the subject of various fields of research. Initially, PON1 was identified as an enzyme capable of hydrolysing organophosphate compounds, but there is a growing body of evidence that PON1 plays a role in lipid metabolism and the onset of cardiovascular disease. Still, the precise mechanism by which PON1 functions in vivo remains to be clarified. Here we will briefly review developments in the field of PON1 research which merit further attention.
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PMID:The story of PON1: how an organophosphate-hydrolysing enzyme is becoming a player in cardiovascular medicine. 1651 86

Human paraoxonase (PON1) exists in 2 major polymorphic forms and has been shown to protect LDL and HDL against oxidation. The aim of this study was to assess the differences between subjects at increased risk of cardiovascular disease (CVD), taking into account the effects of PON1-Q192R and PON1-L55M polymorphisms on 1) basal serum arylesterase activity, lipid peroxidation (LPO), and LDL-cholesterol (LDL-C), HDL-C, total cholesterol (TC), and oxidized-LDL (ox-LDL) concentrations; 2) the relations between arylesterase activity and lipid variables; and 3) the effect of walnut-enriched meat (WM) consumption on arylesterase activity and lipid variables. Twenty-three Caucasians at increased risk of CVD were randomly assigned to diet order groups in a crossover, nonblinded, placebo-controlled trial, consisting of two 5-wk experimental periods [WM and control meat (CM)]. Significant PON1-L55M x PON1-Q192R interactions affected basal serum HDL-C (P = 0.019), LDL-C (P = 0.028) and TC (P = 0.022) and tended to affect arylesterase activity (P = 0.083). Basal arylesterase activity was positively correlated with basal HDL-C (r = 0.53; P < 0.05) and TC (r = 0.43; P < 0.05) and negatively correlated with LPO (r = -0.70; P < 0.01) and the ox-LDL:LDL ratio (r = -0.63; P < 0.01). WM decreased arylesterase activity in PON1-55M carriers (P = 0.012) but not in PON1-L55 individuals, and decreased LPO concentrations in PON1-192R carriers (P = 0.031) but not in PON1-Q192 subjects. To conclude, serum TC, HDL-C, and LDL-C concentrations and arylesterase activity depend on the interaction of PON1-L55M and PON1-Q192R polymorphisms. However, the PON1-Q192R polymorphism is more closely related to antioxidant status. Both polymorphisms modulate the effect of WM consumption on CVD biomarkers.
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PMID:Arylesterase activity and antioxidant status depend on PON1-Q192R and PON1-L55M polymorphisms in subjects with increased risk of cardiovascular disease consuming walnut-enriched meat. 1758 31

Human serum paraoxonase (PON1) is a high-density lipoprotein-associated esterase that protects against organophosphate neurotoxicity, and is proposed to play a role in lipid metabolism and the onset of cardiovascular disease. In the present study, paraoxonase activities and phenotype distribution in serum of 132 healthy Iranian individuals aged 17-68 years were assessed using dual substrate method. In the study population, a wide interindividual variability (up to 15-fold) of paraoxonase activity was found. The mean of basal, salt-stimulated paraoxonase and arylesterase activities were 81.8 +/- 57 U/ml, 153.1 +/- 117.5 U/ml and 80.7 +/- 12.8 kU/l, respectively. The ratio of salt-stimulated paraoxonase activity to arylesterase activity was used for definition of phenotypes. Based on the observed ratios, three distinct phenotypes AA (low activity), AB (intermediate activity) and BB (high activity) were determined. The PON1 ratio varied from 0.5 to 6.8. The paraoxonase phenotype frequencies were approximately 48% (AA), 41% (AB) and 11% (BB). In this work, serum triglycerides had significant positive correlation (r = 0.334, P < 0.05) with paraoxonase activity, whereas high-density lipoprotein did not. No significant decrease in paraoxonase activity by smoking was observed. Age and sex had no influences on PON1 activities. In conclusion, the distribution of paraoxonase phenotypes in this Iranian population was trimodal and comparable to that of Caucasians from North America; however, overall enzyme activity was lower than that reported for Caucasians.
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PMID:Paraoxonase phenotype distribution in a healthy Iranian population. 1765 11

There is strong evidence from both animal- and in vitro-models that paraoxonase (PON1) is involved in the onset of cardiovascular disease. In humans there is no consensus on this issue and therefore we investigated the effect of PON1 genotype and activity on the incidence of coronary heart disease (CHD) and acute myocardial infarction (AMI) in a large prospective cohort of 17,357 middle-aged women. We applied a case-cohort design using the CHD (n=211) and AMI cases (n=71) and a random sample from the baseline cohort (n=1527). A weighted Cox proportional hazards model was used to estimate age- and multivariate-adjusted hazard ratios (HR) for the PON1 genetic variants (192Q > R and -107C > T) and tertiles of the PON1 arylesterase- and paraoxonase activities. Neither the PON1 genetic variants, nor the PON1 activities affected the incidence of CHD in general, but, an increased paraoxonase activity was associated with a higher risk of AMI: the second and third tertile HR were 1.31 and 2.07, respectively (P-trend=0.029, multivariate model). In the subgroup of never-smokers, paraoxonase activity was associated with an increased risk for AMI: the second and third tertile HR were 4.1 and 4.7, respectively (P-trend=0.009, multivariate model). Additionally, when compared to the lowest paraoxonase tertile in never-smokers, the highest paraoxonase tertile in current-smokers showed a 19.2-fold higher risk for AMI (95%CI: 5.3-69.5, P < 0.0001, multivariate model). In conclusion, this study shows that in middle-aged women paraoxonase activity was associated with an increased risk for AMI and that the risk was modified by the effects of smoking.
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PMID:Paraoxonase (PON1) and the risk for coronary heart disease and myocardial infarction in a general population of Dutch women. 1816 14


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