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)

Human serum paraoxonase (PON1) associated with high density lipoprotein (HDL) has been postulated to have a role in protecting low density lipoprotein (LDL) against oxidative modification, which has led to the proposal that PON1 is an anti-atherogenic, anti-inflammatory enzyme. PON1 has two genetically determined polymorphic sites giving rise to amino-acid substitutions at positions 55 (L-->M) and 192 (R-->Q) and therefore 4 potential alloenzymes. We have examined the effects of these molecular polymorphisms on the ability of HDL to protect LDL from oxidative modification. HDL protected LDL from oxidative modification, whatever the combination of PON1 alloenzymes present in it. However, HDL from QQ/MM homozygotes was most effective at protecting LDL while HDL from RR/LL homozygotes was least effective. Thus after 6 h of co-incubation of HDL and LDL with Cu2+ PON1-QQ HDL retained 57 +/- 6.3% of its original ability to protect LDL from oxidative modification, while PON1-QR HDL retained less at 25.1 +/- 4.5% (P < 0.01) and PON1-RR HDL retained only 0.75 +/- 0.40% (P < 0.005). In similar experiments HDL from LL and LM genotypes retained 21.8 +/- 7.5% and 29.5 +/- 6.6% (P = NS), respectively, of their protective ability, whereas PON1-MM HDL maintained 49.5 +/- 5.3% (P < 0.01). PON1 polymorphisms may affect the ability of HDL to impede the development of atherosclerosis and to prevent inflammation.
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PMID:Effect of the human serum paraoxonase 55 and 192 genetic polymorphisms on the protection by high density lipoprotein against low density lipoprotein oxidative modification. 950 41

Serum paraoxonase (PON1) is an esterase that is associated with high-density lipoproteins (HDLs) in the plasma; it is involved in the detoxification of organophosphate insecticides such as parathion and chlorpyrifos. PON1 may also confer protection against coronary artery disease by destroying pro-inflammatory oxidized lipids present in oxidized low-density lipoproteins (LDLs). To study the role of PON1 in vivo, we created PON1-knockout mice by gene targeting. Compared with their wild-type littermates, PON1-deficient mice were extremely sensitive to the toxic effects of chlorpyrifos oxon, the activated form of chlorpyrifos, and were more sensitive to chlorpyrifos itself. HDLs isolated from PON1-deficient mice were unable to prevent LDL oxidation in a co-cultured cell model of the artery wall, and both HDLs and LDLs isolated from PON1-knockout mice were more susceptible to oxidation by co-cultured cells than the lipoproteins from wild-type littermates. When fed on a high-fat, high-cholesterol diet, PON1-null mice were more susceptible to atherosclerosis than their wild-type littermates.
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PMID:Mice lacking serum paraoxonase are susceptible to organophosphate toxicity and atherosclerosis. 968 59

In a sample taken from the genetically isolated Alberta Hutterites, we previously found that PON1 variation was associated with variation in plasma lipoprotein traits, including LDL and HDL cholesterol. With the recent cloning of the PON1-related gene PON2, we undertook studies of the association between genetic variation in PON2 and variation in plasma quantitative traits variation in a sample of 745 Alberta Hutterites. We found novel genetic associations between PON2 variation and variation in fasting plasma concentrations of total cholesterol and apolipoprotein AI. We confirmed our previously observed significant associations in this study sample between PON1 genetic variation and variation in plasma apo B-related traits, such as LDL, non-HDL and HDL cholesterol and apo B itself. Furthermore, there was almost complete linkage disequilibrium between PON2 alleles G148 and C311. We found no association between PON2 variation and plasma glucose or insulin. Taken together, our results suggest that common genetic variation on chromosome 7q21.3-22.1 in both PON1 and PON2 that affects the amino acid sequence of the respective gene products is associated with significant variation in intermediate traits in plasma lipoprotein metabolism.
Atherosclerosis 1998 Jul
PMID:Genetic variation in paraoxonase-1 and paraoxonase-2 is associated with variation in plasma lipoproteins in Alberta Hutterites. 969

1. Human serum paraoxonase (PON1) is a Ca2+-dependent 45-kDa glycoprotein that is associated with high density lipoprotein (HDL). 2. PON1 hydrolyzes organophosphate (OP) insecticides and nerve gases and is responsible for determining the selective toxicity of these compounds in mammals. 3. PON1 has two genetic polymorphisms giving rise to amino acid substitutions at positions 55 and 192. The position-192 polymorphism is the major determinant of the PON1 activity polymorphism. However, the position-55 polymorphism also modulates activity. 4. Genotyping individuals for both PON1 polymorphisms may provide a method for identifying those most at risk of OP poisoning. The effect of the PON1 polymorphisms on activity may explain why some Gulf War veterans have developed Gulf War syndrome and some have not, despite similar OP exposure. 5. PON1 may also be a determinant of resistance to the development of atherosclerosis by protecting lipoproteins against oxidative modification, perhaps by hydrolyzing phospholipid hydroperoxides. 6. The PON 1 polymorphisms are important in determining the capacity of HDL to protect low density lipoprotein against oxidative modification in vitro, which may explain the relation between the PON1 alleles and coronary heart disease in case-control studies.
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PMID:Human serum paraoxonase. 970 97

Numerous epidemiological studies have suggested an association between the acute phase response and atherosclerosis. Paraoxonase (PON) is an HDL associated enzyme that protects LDL from oxidative stress. Here we demonstrate that serum PON activity decreases following endotoxin (LPS) administration in Syrian hamsters. This decrease is seen within 24 h following LPS treatment and doses as low as 100 ng/100 g body weight of LPS elicit a reduction in serum PON activity. LPS also induces a marked decrease in PON1 mRNA in the liver (80% decrease). The decrease in mRNA levels is observed as early as 4 h and is sustained for at least 48 h after a single LPS treatment. Moreover, TNF and IL-1, cytokines which mediate the acute phase response, also decrease serum PON activity and PON mRNA levels in the liver. Additionally, TNF and IL-1 treatment of HepG2 cells results in a decrease in PON mRNA levels indicating that these cytokines are capable of directly affecting liver cells. Along with other changes in lipid metabolism that occur during the acute phase response, the decrease in PON could be another factor linking the acute phase response with increased atherogenesis.
Atherosclerosis 1998 Aug
PMID:Paraoxonase activity in the serum and hepatic mRNA levels decrease during the acute phase response. 971 37

Human serum paraoxonase (PON1) is located on high density lipoprotein and has been implicated in the detoxification of organophosphates and possibly in the prevention of low density lipoprotein lipid peroxidation. PON1 has two genetic polymorphisms both due to amino acid substitution, one involving glutamine (A genotype) and arginine (B genotype) at position 192 and the other leucine (L genotype) and methionine (M genotype) at position 55. We investigated the effect of these polymorphisms on serum PON1 activity and concentration in 252 non-insulin dependent diabetes mellitus (NIDDM) individuals and 282 non-diabetic controls. Serum PON1 activity in the controls (214.6 nmol/min per ml (26.3-620.8)) was significantly higher than in NIDDM (158.7 nmol/min per ml (3.6-550.5) (P < 0.001) as was serum PON1 concentration (89.1 microg/ml (16.8-527.4)) compared to 76.7 microg/ml (3.6-443.8) (P < 0.01). In the control population MM homozygotes had significantly lower serum PON1 activity regardless of the 192 polymorphism whereas in NIDDM both LM and MM genotypes had lower serum PON1 activity than LL homozygotes only when the 192 AA genotype was present. Serum PON1 concentration was lower in NIDDM with AA/LM, AA/LL, AB/LL and AB/MM genotypes than in controls. Differences in PON1 activity were the major cause of differences in specific activity between genotypes. Neither the PON1 55 or 192 polymorphisms consistently influenced the serum lipid or lipoprotein concentrations in either population. Low serum PON1 activity in NIDDM may be related to an increased tendency to lipid peroxidation and may also increase susceptibility to toxicity from organophosphate exposure. Our findings thus raise the possibility that PON1 may be of importance in both the genetic and acquired predisposition to premature atherosclerosis and neuropathy in diabetes.
Atherosclerosis 1998 Aug
PMID:Serum paraoxonase (PON1) 55 and 192 polymorphism and paraoxonase activity and concentration in non-insulin dependent diabetes mellitus. 971 41

Paraoxonase (PON1) hydrolyses organophosphate insecticides and nerve gases and is responsible for determining the selective toxicity of these compounds in mammals. Human PON1 has two genetic polymorphisms giving rise to amino-acid substitutions at positions 55 and 192. The 192 polymorphism is the major determinant of the PON1 activity polymorphism towards organophosphates. However, the 55 polymorphism also modulates activity. Ex vivo, the PON1 polymorphisms are important in determining the capacity of HDL to protect LDL against oxidative modification in vitro and this may explain the relationship between the PON1 alleles and coronary heart disease in case-control studies. In recent case-control studies serum PON1 concentration and activity were also found to be decreased in coronary heart disease (CHD) independent of the PON1 polymorphism, and in diabetes serum PON1 specific activity decrease is also independent of the PON1 genetic polymorphism. HDL from transgenic mice lacking PON1 fails to protect LDL against oxidative modification. Thus PON1 may be a determinant of resistance to the development of atherosclerosis by protecting lipoproteins against oxidative modification, perhaps by hydrolysing phospholipid and cholesteryl-ester hydroperoxides.
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PMID:Paraoxonase and coronary heart disease. 973 87

Serum paraoxonase (PON) is an HDL-bound enzyme protecting LDL from oxidation. A common polymorphism of the paraoxonase gene (PON1) involving a Gln-to-Arg interchange at position 192 has been demonstrated to modulate PON activity toward paraoxon, a nonphysiological substrate; Arg192 (allele B) is associated with higher activity than Gln192 (allele A). This polymorphism has been proposed as a genetic marker of risk for coronary artery disease (CAD). However, the relationships between codon 192 PON1 genotypes, coronary atherosclerosis, and the occurrence of myocardial infarction (MI) are still controversial. PON1 genotypes were determined in 472 consecutive subjects (>40 years old) who underwent coronary angiography. CAD (>50% stenosis) was detected in 310 subjects (CAD+); 162 subjects with <10% stenosis served as controls (CAD-). We also evaluated 204 randomly selected individuals as population controls. PON1 genotypes were determined by PCR and AlwI restriction enzyme digestion. Frequencies of alleles A and B were 0. 70 and 0.30 in angiographically assessed subjects and 0.73 and 0.27 in population controls, respectively (chi2=2.0; P<0.3). Distribution of PON1 genotypes in CAD+ were not significantly different from those in CAD- (chi2=2.10; P<0.3). Similarly, no differences were observed in the subgroup of CAD+ with MI nor in that at higher oxidative risk (smokers and/or diabetics). After controlling for other coronary risk factors, no association was found between PON1 alleles and the presence of CAD. PON1 AA genotype was associated with reduced concentration of apolipoprotein B-containing triglyceride-rich lipoproteins. This study did not provide evidence of a significant association between codon 192 PON1 genotypes and coronary atherosclerosis in Italian patients. However, it did confirm that the PON1 low-activity allele is associated with a less atherogenic lipid profile.
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PMID:The gln-Arg192 polymorphism of human paraoxonase gene is not associated with coronary artery disease in italian patients. 976 34

Paraoxonase (PON1) is a high density lipoprotein-associated enzyme capable of hydrolyzing lipid peroxides, and thus, might protect lipoproteins from oxidation. A common polymorphism due to an amino acid substitution (Gln-Arg) at codon 191 is considered to be a major determinant of variation in serum PON1 activity. Recent studies have suggested that the PON1-191 polymorphism is an independent risk factor for coronary atherosclerosis in patients with or without diabetes mellitus. The association of PON1-191 polymorphism genotypes and coronary artery disease (CAD) among Chinese subjects in Taiwan was examined. The genotype of 218 angiographically documented CAD patients and the same number of age- and sex-matched control subjects was determined. Genotypes AA, AB and BB were present in 25 (11%), 102 (47%) and 91 (42%) of control subjects, respectively, and in 30 (14%), 96 (44%) and 92 (42%) of CAD patients, respectively (chi2 = 0.57, P = 0.75 between groups). The frequency of the A allele was 0.36 for the control group and 0.35 for CAD patients (P = 0.94). No significant differences in the PON1-191 genotype frequencies could be found between groups when multivariate logistic regression analysis was performed, or different subgroups of age, sex or risk factors were analyzed. Among control subjects, there was also no significant difference between genotypes of the PON1-191 polymorphism and various clinical and lipid variables. In conclusion, our data suggest that there is no association between the Gln-Arg 191 polymorphism of the human PON1 gene and CAD among Chinese subjects in Taiwan.
Atherosclerosis 1998 Dec
PMID:The Gln-Arg 191 polymorphism of the human paraoxonase gene is not associated with the risk of coronary artery disease among Chinese in Taiwan. 986 74

HDL has been shown to prevent the oxidative modification of LDL. The antioxidant activity of HDL is believed to reside in its enzymes, particularly paraoxonase. Human serum paraoxonase (PON1) is closely associated with a specific HDL subfraction also containing apoA1 and clusterin. Recently PON1 has been implicated in the pathogenesis of atherosclerosis. We have examined the activity, concentration, and specific activity of PON1 in 50 patients on admission to hospital immediately after acute myocardial infarction (MI) and in 48 age- and gender-matched controls. Serum PON1 activity and concentration were significantly lower in patients with MI than in controls (activity, 221.5 [99.3 to 303.2] nmol. min-1. mL-1 in controls and 130.1 [78.9 to 230.3] nmol. min-1. mL-1 in MI patients [P<0.05]; concentration, 95.7 [73.2 to 135.5] microg/mL in controls and 35.4 [21.6 to 51.3] microg/mL in MI patients [P<0.001]). PON1-specific activity was significantly higher in patients with MI than in controls (1.5 [0.9 to 2.9] versus 3.4 [2.0 to 8.5] nmol. min-1. microg-1 [P<0.001]) due to the much lower PON1 concentration. PON1 activity had risen significantly (P<0.05) to 158.1 (85.4 to 282.0) nmol. min-1. mL-1 at day 42 but was still significantly less than that of controls. No significant variation in PON1 concentration occured in the days after MI or at 6 weeks. Also, no significant variation in specific activity was seen after MI. When the patients were divided into subgroups based on whether or not they received thrombolytic therapy on admission to hospital, no significant difference in PON1 levels was observed. Serum HDL cholesterol in patients with MI on admission was not significantly different than in controls, and the decrease that occurred by the fifth day after MI did not explain the lower PON1 levels. We conclude that low serum PON1 activity in patients with MI may be a consequence of the coronary event itself or could have been present before MI. The low PON1 activity was also not explicable on the basis of PON1 genotypes because the prevalence of genotypes associated with low activity was not sufficient to explain fully the difference in activity levels between patients and controls. The explanation for the low PON1 activity was most likely a decrease in serum PON1 concentration. The importance of PON1 as a predictive risk factor for MI should be assessed in future studies.
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PMID:Serum paraoxonase after myocardial infarction. 997 15


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