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)

Paraoxonase-1 (PON-1) is a high-density lipoprotein (HDL)-associated enzyme that hydrolyzes oxidized phospholipids, thereby preventing the oxidative modification of low-density lipoproteins (LDL). A high-fat diet reduces PON-1 activity, enhancing LDL oxidation. Thus, PON-1 is a candidate for anti-atherogenic gene therapy. In the present study, we investigated the effect of local PON-1 overexpression on the development of atherosclerotic lesions using the Sendai virus-mediated transgenic technique. One-month-old rabbits (n=11) were fed a high-fat diet for 8 weeks and then subjected to balloon injury of the common iliac artery and simultaneous infection with a Sendai virus vector containing the PON-1 gene (n=7) or enhanced green fluorescence protein (EGFP) gene as a control (n=4). The arteries were examined 7-10 days after the operation. Local overexpression of PON-1 almost completely eliminated the immunohistochemical signals of the lectin-like oxidized LDL receptor-1 (LOX-1), thereby inhibiting macrophage accumulation, intimal thickening (by 63% compared with control), or atherosclerotic plaque formation in the vascular lumen (by 87.5%). Decreased levels of oxidative stress in the PON-1-treated arteries were confirmed by 4-hydroxy-2-nonenal (HNE) staining. Local overexpression of PON-1 in the arteries attenuated oxidative stress, thereby inhibiting the atherosclerotic process. Delivery of the PON-1 gene may be a possible therapeutic strategy for preventing atherosclerosis.
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PMID:Gene delivery of paraoxonase-1 inhibits neointimal hyperplasia after arterial balloon-injury in rabbits fed a high-fat diet. 1746 Mar 75

Homocysteine (Hcy)-thiolactonase (HTase) activity of the paraoxonase-1 (PON1) protein detoxifies Hcythiolactone in human blood and could thus delay the development of atherosclerosis. We investigated a hypothesis that HTase activity is associated with coronary heart disease. We studied HTase activities and PON1 genotypes in a group of 475 subjects, 42.5% of whom were healthy and 57.5% had coronary heart disease (CHD). We found that HTase activity was positively correlated with total cholesterol (r=0.254, P<0.0001), LDL cholesterol (0.149, P=0.016), ApoB (r=0.167, P=0.006), ApoA1 (0.140, P=0.023), and HDL cholesterol (0.184, P=0.002) in a group of CHD cases (n=270) but not in controls (n=202). Mean HTase activity was significantly higher in CHD cases than in controls (4.57 units vs. 3.30 units, P <10(-5)). The frequencies of the PON1-192 genotypes in CHD cases were similar to those in controls. HTase activity was not different between patients receiving statins and those not treated with statins. Multiple regression analysis shows that CHD status, PON1 genotype, and total cholesterol are determinants of HTase activity in humans. Our results suggest that HTase activity of the PON 1 protein is a predictor of CHD.
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PMID:The correlation of homocysteine-thiolactonase activity of the paraoxonase (PON1) protein with coronary heart disease status. 1754 99

Diets consumed in industrialized countries are rich in fat and increase the incidence of atherosclerosis, a process reported to be influenced by gender. Considering the anti-atherogenic role attributed to serum Paraoxonase 1 (PON1) activity, and given the pro-atherogenic effects described for saturated fatty acids (SFA), as opposed to the beneficial ones conferred to monounsaturated fatty acids (MUFA), the aim of this study was to investigate the response of male and female rat serum PON1 activity and its related factors to a high-fat (HF), hypercaloric diet (fat representing 55.2% of the energy) containing similar amounts of SFA and MUFA. The HF diet feeding did not alter total body weight, but increased adiposity. Nevertheless, and in spite of the increased adiposity, the HF diet did not entail a more pro-inflammatory serum adipokine or lipid profile or increased lipid peroxidation. Paraoxonase activity was reduced in both male and female HF fed rats, due to a reduction of PON1 mRNA levels in males and to a reduced stability and/or number of HDL particles responsible for PON1 transport in females. Both the maintenance of body weight and the MUFA content in the diet would be among the factors responsible for the attenuation of the negative effects usually related to excessive fat intake and for the reduction in PON activity, whose antioxidant activity would be less necessary in this situation.
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PMID:Paraoxonase 1 response to a high-fat diet: gender differences in the factors involved. 1759 56

The low density lipoprotein (LDL) oxidation hypothesis has generated considerable interest in oxidative stress and how it might affect atherosclerosis. However, the failure of antioxidants, particularly vitamin E, to affect the progression of the disease in humans has convinced even staunch supporters of the hypothesis to take a step backwards and reconsider alternatives. Preponderant evidence for the hypothesis came from animal antioxidant intervention studies. In this review we point out basic differences between animal and human atherosclerosis development and suggest that human disease starts where animal studies end. While initial oxidative steps in the generation of early fatty streak lesions might be common, the differences might be in the steps involved in the decomposition of peroxidized lipids into aldehydes and their further oxidation into carboxylic acids. We suggest that these steps may not be amenable to attenuation by antioxidants and antioxidants might actually counter the stabilization of plaque by preventing the formation of carboxylic acids which are anti-inflammatory in nature. The formation of such dicarboxylic acids may also be conducive to plaque stabilization by trapping calcium. We suggest that agents that would prevent the decomposition of lipid peroxides and promote the formation and removal of lipid hydroxides, such as paraoxonase (PON 1) or apo A1/high density lipoprotein (HDL) might be more conducive to plaque regression.
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PMID:Lipid peroxidation and decomposition--conflicting roles in plaque vulnerability and stability. 1840 61

The metabolic syndrome is a common and complex disorder combining obesity, dyslipidemia, hypertension, and insulin resistance. It is a primary risk factor for diabetes and cardiovascular disease. We showed for the first time that the metabolic syndrome is associated with a higher fraction of oxidized LDL and thus with higher levels of circulating oxidized LDL. Hyperinsulinemia and impaired glycaemic control, independent of lipid levels, were associated with increased in vivo LDL oxidation, as reflected by the higher prevalence of high oxidized LDL. High levels of oxidized LDL were associated with increased risk of future myocardial infarction, even after adjustment for LDL-cholesterol and other established cardiovascular risk factors. This association is in agreement with the finding that accumulation of oxidized LDL, which activates/induces subsets of smooth muscle cells and macrophages to gelatinase production, was associated with upstream localization of a vulnerable plaque phenotype. Dyslipidemia and insulin resistance in obese LDL receptor-deficient mice were associated with increased oxidative stress and impaired HDL-associated antioxidant defence associated with accelerated atherosclerosis due to increased macrophage infiltration and accumulation of oxidized LDL in the aorta. The accumulation of oxidized LDL was partly due to an impaired HDL-associated antioxidant defence due to a decrease in PON. Our data in this experimental model are thus the more relevant because a decrease in PON activity was found to be associated with a defective metabolism of oxidized phospholipids by HDL from patients with type 2 diabetes. Weight loss in leptin-deficient, obese, and insulin-resistant mice was associated with expressional changes of key genes regulating adipocyte differentiation, glucose transport and insulin sensitivity, lipid metabolism, oxidative stress and inflammation, most of which are under the transcriptional control of PPARs. We established an important relationship between PPAR-gamma and SOD1 for the prevention of the oxidation of LDL in the arterial wall. For example we showed that rosuvastatin decreased the oxidized LDL accumulation by increasing the expression of PPAR-gamma and SOD1. In addition, we established a relation between increased PPAR-alpha expression in the adipose tissue and a change in the gene expression pattern, which explains the decrease of free fatty acids, triglycerides and the increase in insulin sensitivity. We demonstrated that plaque oxidized LDL correlated with coronary plaque complexity in a swine atherosclerosis model. Oxidized LDL correlated positively with the expression of IRF1 and TLR2 suggesting a relation between oxidative stress and inflammation in coronary atherosclerotic plaques. Oxidized LDL induced further the expression of TLR2 and IRF1 in macrophages in vitro suggesting a causative link. As in the mouse model described above, plaque oxidized LDL correlated negatively with SOD1 expression and ox-LDL inhibited the expression of SOD1 in macrophages in vitro. We showed that TLR2, CXCR4 and MYC are overexpressed in monocytes of obese women at high cardiovascular risk and that weight loss was associated with a concomitant decrease of their expression. This suggests that the transcription factor cMYC has an atherogenic effect by inducing pro-inflammatory genes. The increased expression of TLR2 and CXCR4 were observed in the absence of an increase in ox-LDL but in the presence of an increase in SOD1. Interestingly, the expression of SOD1 correlated also with that of MYC, suggesting that it has an atherogenic effect by inducing the expression of an anti-oxidant enzyme. How ox-LDL prevents this increase remains to be determined. How we plan to do this is explained in the next part. In aggregate, our studies contributed to a better understanding of the relationships between metabolic syndrome, insulin signalling, oxidative stress and inflammation and atherosclerosis. We identified paraoxonase, interferon regulatory factor-1, toll-like receptors, CXCR4 and SOD1 as possible targets for intervention.
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PMID:Relations between metabolic syndrome, oxidative stress and inflammation and cardiovascular disease. 1866 60

The association of polymorphisms affecting lipid metabolism with the risk of myocardial infarction (MI) in type 2 diabetes mellitus was investigated. The Genetics, Outcomes and Lipids in type 2 Diabetes (GOLD) Study is a prospective, multicenter study, conducted on 990 patients presenting diabetes and MI (n=386), or diabetes without previous manifestation of stroke, peripheral or coronary arterial disease (n=604), recruited from 27 institutions in Brazil. APO A1 (A/G -75 and C/T +83) and APO C3 (C/G 3'UTR) non-coding sequences, CETP (Taq 1B), LPL (D9N), APO E (epsilon2, epsilon3, epsilon4,), PON-1 (Q192R), and two LCAT variants Arg(147)-->Trp and Tyr(171)-->Stop were tested by PCR-RFLP. There was a higher prevalence of LPL DN genotype (19% vs.12%, p=0.03) and a higher frequency of the N allele (11% vs. 7%) among subjects with MI when compared to controls, with an odds ratio of MI for carriers of 9N allele of 2.46 (95% CI=1.79-3.39, p<0.0001). This association was present in men and women, in non-smokers and in hypertensive patients. A logistic regression model including gender, duration of diabetes, systolic blood pressure, HDL-C, left ventricle hypertrophy and D9N polymorphism showed that the latter still remained significantly associated with MI (OR=1.50, 95% CI=1.02-2.25, p=0.049). These findings suggest that D9N polymorphism can be a useful risk marker for myocardial infarction and that further potential candidate genes should be screened for exploratory analysis and for future therapeutic intervention in diabetes.
Atherosclerosis 2009 May
PMID:Association of lipoprotein lipase D9N polymorphism with myocardial infarction in type 2 diabetes: the genetics, outcomes, and lipids in type 2 diabetes (GOLD) study. 1882 27

Mammalian paraoxonases (PON1, PON2, PON3) are a unique family of calcium-dependent hydrolases, with enzymatic activities toward a broad range of substrates (lactones, thiolactones, carbonates, esters, phosphotriesters). Although PONs physiological substrates were not yet identified, some studies suggest that they could be some lactones, or some specific oxidized phospholipids, or products of both enzymatic and nonenzymatic oxidation of arachidonic and docosahexaenoic acid, as well as N-acyl-homoserine lactones (which are quorum-sensing signals of pathogenic bacteria). Since no endogenous substrates for PONs activity determination are available yet, synthetic substrates such as paraoxon, phenyl acetate, and several lactones are used for PONs activity assays. All three members of the PON family (PON 1/2/3) were shown to protect from atherosclerosis development. Their anti-atherogenic biological activities were studied in vitro using serum or cell cultures, and also in vivo, using PON 1/2/3 knockout or transgenic mice, as well as humans - healthy volunteers and atherosclerotic patients (diabetics, hypercholesterolemics, and hypertensives).
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PMID:Paraoxonases (PON1, PON2, PON3) analyses in vitro and in vivo in relation to cardiovascular diseases. 1908 53

To understand whether human paraoxonase 1 (PON1) would modulate the risk for arsenic-related atherosclerosis, we studied 196 residents from an arseniasis-endemic area in Southwestern Taiwan and 291 age- and sex-matched residents from a nearby control area where arsenic exposure was found low. Carotid atherosclerosis was defined by a carotid artery intima-media wall thickness (IMT) of >1.0 mm. Prevalence of carotid atherosclerosis was increased in the arseniasis-endemic area as compared to the control area after adjustment for conventional risk factors (OR=2.20, p<0.01). The prevalence was positively associated with cumulative arsenic exposure (mg/L-year) in a dose-dependent manner. Multiple logistic regression analysis showed that in the endemic group, low serum PON1 activity was an independent risk factor for atherosclerosis (OR=4.18 low vs. high, p<0.05). For those of low PON1 activity and high cumulative arsenic exposure, the odds ratio for the prevalence of atherosclerosis was further increased up to 5.68 (p<0.05). No significant association was found between atherosclerosis and four polymorphisms of the PON gene cluster (PON1 -108C/T, PON1 Q192R, PON2 A148G, PON2 C311S). However, genetic frequencies of certain alleles including PON1 Q192, PON2 G148 and PON2 C311 were found increased in the endemic group as compared to the controls and a general Chinese population, indicating a possible survival selection in the endemic group after a long arsenic exposure history. Our results showed a significant joint effect between arsenic exposure and serum PON1 activity on carotid atherosclerosis, suggesting that subjects of low PON1 activity may be more susceptible to arsenic-related cardiovascular disease.
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PMID:Risk of carotid atherosclerosis is associated with low serum paraoxonase (PON1) activity among arsenic exposed residents in Southwestern Taiwan. 1937 7

Paraoxonase 1 (PON1) is thought to influence serum homocysteine concentrations, at least in part, due to its homocysteine thiolactonase activity and to play a role in preeclampsia and atherosclerosis. We investigated the effects of PON 55 and PON 192 polymorphisms on plasma total homocysteine (tHcy) concentrations in preeclamptic and healthy pregnants among Turkish population (N = 106). PON 55 and 192 genotypes were determined by PCR RFLP techniques. Plasma tHcy concentrations were measured by high-performance liquid chromatography. No differences were observed in the distribution of PON 1 55/192 genotypes and allele frequencies between the preeclamptic and healthy pregnants. tHcy level in the plasma of preeclamptic women was found to be increased in comparison with healthy pregnants (P < 0.01). Preeclamptic women bearing the mutated PON 192 RR and wild-type PON1 55 LL genotypes had higher tHcy levels than those of the healthy pregnants with the corresponding genotypes, supporting the possibility that the hyperhomocysteinaemia seen in preeclamptic women is associated with the PON genotypes. However, no influence of the allelic distribution on plasma tHcy concentrations was detected in either group. Our results suggest that PON1 55 and 192 genotypes might have an important role in developing hyperhomocysteinaemia and may also have a role in the pathogenesis of preeclampsia in a Turkish population.
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PMID:Association of paraoxonase 55 and 192 gene polymorphisms on serum homocysteine concentrations in preeclampsia. 1945 76

Paraoxonase-1 (PON-1), an HDL-associated enzyme has been shown to possess antioxidant/anti-inflammatory properties and protect against atherogenesis. The aim of the study was to explore the association of PON-1, with lipids, antioxidant-vitamins and lifestyle in male subjects with and without angiographically documented coronary artery disease (CAD) and in healthy volunteers. PON-1 activity was measured spectrophotometrically using phenyl acetate as substrate. PON-1 and HDL-Cholesterol were significantly lower and lipid peroxides and triglycerides were higher in CAD patients than in normal coronary and control subjects. PON-1 activity showed positive association with HDL-C and inverse relation with lipid peroxides and no association with antioxidant vitamins in healthy subjects. Smoking habit, alcohol intake and diabetes mellitus did not seem to influence PON-1 activity. Serum levels of PON-1 and HDL-C showed inverse association with the presence of CAD but are not related to the severity of disease in terms of number of diseased vessels. Interventional means by diet/drugs to enhance PON-1 activity may contribute to attenuation of atherosclerosis.
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PMID:High prevalence of low serum paraoxonase-1 in subjects with coronary artery disease. 1990 17


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