Is Paraoxonase-3 Another HDL-Associated Protein Protective Against Atherosclerosis?
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Arteriosclerosis, Thrombosis, and Vascular Biology is the first report of expression of human paraoxonase-3 (PON3) and its ability to prevent the formation of mildly oxidized LDL and also to inactivate preformed mildly oxidized LDL.Keywords:
Paraoxonase
Aryldialkylphosphatase
Abstract We examined levels of malondialdehyde (MDA) (an end‐product of lipid peroxidation) and paraoxonase (PON1) (an antioxidant enzyme) activity and PON1 phenotypes in people who were exposed to ionizing radiation for different time periods and doses. A total of 78 individuals (mean age 34 ± 7 years) were included in the study. Fifty‐one of them were radiology workers whereas the control group was composed of 27 healthy volunteers who had never worked in a radiology‐related job. Paraoxon was used as substrate for measurement of PON1 activity levels (basal and NaCl‐stimulated). Phenylacetate was used as substrate for measurement of arylesterase activity levels. Cumulative levels of serum NaCl‐stimulated PON1/arylesterase activities were utilized for phenotypic differentiation. In radiology workers, three different phenotypes were determined based on paraoxonase/arylesterase ratio. The ratios were 1.09 ± 0.30 for AA (homozygote low activity); 2.91 ± 1.07 for AB (heterozygote activity) and 4.97 ± 1.21 for BB (homozygote high activity). There was a statistically meaningful negative correlation between serum MDA levels and PON1 activity levels in all phenotypes ( p < 0.05). PON1 activity levels were found to be 25–35% lower in people who were exposed to long‐term ( > 5 years) radiation compared to controls. There was no statistically significant correlation between serum arylesterase activity and MDA levels in these subjects ( r = −0.185, p > 0.05). PON1 activity levels were decreased whereas serum MDA levels were increased in individuals exposed to radiation for a long period. PON phenotypes of people employed in jobs which expose them to radiation should be determined and based on these findings they should be advised to avoid risk factors inducing oxidative stress, such as smoking, and to consume foods rich in vitamins and trace elements to increase their antioxidant capacity. Copyright © 2003 John Wiley & Sons, Ltd.
Arylesterase
Paraoxonase
Malondialdehyde
Aryldialkylphosphatase
Paraoxon
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P.1.38 Effects of paraoxonase 1 (PON1) genotype and nanomaterials exposure on heart rate variability
Background Although paraoxonase 1 (PON1) is a high-density lipoprotein (HDL) associated antioxidant enzyme that has beneficial effects on atherosclerosis and cardiovascular disease, whether PON1 Q192R polymorphism have any effect on cardiac autonomic function is yet to be investigated. Moreover, there is limited data regarding the influence of NPs exposure on HRV parameters in humans. The purpose of the study was to exam whether PON1 genotype or NPs exposure has an association with HRV levels. Methods This cross-sectional study recruited 235 workers exposed to NM and 185 non-exposed controls from 14 NM handling plants in Taiwan from 2009 to 2011. For each participant, we collected blood specimens to determine the genotype of the PON1 Q192R polymorphism and PON1 paraoxonase and arylesterase activities. In addition, short-term HRV was tested. Results The results showed that PON1 Q192R genotype and PON1 paraoxonase/arylesterase activities associated with HRV, and was particularly noteworthy in RMSSD and HF. The relationship between NPs exposure and HRV was only found in workers exposed to nano-Ag, but the apparent relationship between NPs exposure and HRV is lacking. Conclusions It is a novel finding that both RR genotype of PON1 (Q192R) and activities of PON1 increased with HRV levels. PON1 Q192R genotype may play an important role in cardiac protection. Considering the global prevalence of NMs market, further studies of NPs-induced cardiac events and stresses still are required to establish.
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Paraoxonase type 1 (PON1) is an enzyme which belongs to the family of paraoxonases. Other members of the paraoxonase family are PON2 and PON3. In the human body, PON1 is located exclusively on the high-density lipoprotein (HDL) particle. As the name 'paraoxonase' indicates, PON1 can hydrolyze the highly toxic organophosphate and insecticide 'paraoxon'. Since paraoxon is a toxic chemical compound, it is not plausible that the hydrolysis of paraoxon is the primary biological function of PON1. Many research groups have previously suggested that the prevention of oxidation of low-density lipoprotein (LDL), is an important beneficial function of PON1 in the human body. Because the oxidation of LDL is one of the first steps in the development of atherosclerosis, the inhibition of LDL oxidation by PON1 may be an important step in the prevention of cardiovascular disease (CVD). There are also indications that PON1 can prevent the oxidation of the HDL particle and as a result preserve the beneficial function of HDL in the reverse cholesterol transport, i.e. the cholesterol efflux from macrophages. Since cholesterol efflux is an important function of the HDL particle, this interaction may also be an important second function of PON1. In this thesis, we have addressed the following questions regarding PON1. 1.) To what extent does PON1 inhibit the oxidation of LDL? 2.) Does PON1 influence the functioning of the HDL particle and as a result the lipid metabolism? 3.) To what extent does PON1 contribute to the onset of CVD. The main outcome of our studies is that, in contrast to what has been frequently suggested by other investigators, we cannot confirm that PON1 plays an important role in the oxidation of LDL in the human body. We do find that PON1 may have other effects which relate to CVD. We find that higher PON1 levels contribute to higher HDL-cholesterol levels in the body, demonstrating a beneficial role for PON1 in the lipid metabolism
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Paraoxon
Aryldialkylphosphatase
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Lipoprotein particle
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Paraoxonase
Aryldialkylphosphatase
Arylesterase
Butyrylcholinesterase
Cholinesterase
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Human serum paraoxonase (PON1) is a high density lipoprotein (HDL)associated enzyme capable of hydrolyzing lipid peroxides in vitro .PON1 has recently attracted attetion as a key factor against oxidative modification of LDL by involving in degradation of oxidized phospholipid and may therefore play an important role on the prevention of the atherosclerotic process of HDL.The concentration and activity of PON1 have been shown to be associated with the risk of atherosclerosis.In addition,the genetic polymorphisms of PON1 have been proposed as a genetic marker of risk for coronary artery disease.The measurement of the genetic polymorphisms of PON1 may be helpful in the prevention of coronary artery disease.
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Aryldialkylphosphatase
High-density lipoprotein
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Paraoxonase (PON1) is a high density lipoprotein (HDL) associated enzyme that is known for its function to hydrolyze organophosphate (OPs) into a relatively harmless substance and prevent atherosclerosis by inhibiting oxidative modification of low density lipoprotein (LDL). In some studies low PON1 activity was reported among individuals who are exposed to OPs, while in different studies low PON1 activity was associated with a high risk of coronary artery disease (CAD). However, the link between OPs exposure and lipid profiles which are known risk factors of CAD has not yet been reported. The aim of our present preliminary study was to compare the activities of PON1 and lipid profiles between the workers who are exposed to OPs and the comparative non-exposed group. This cross sectional comparative study was carried out on a total of 105 subjects comprising of 53 OPs exposed group and 52 comparative non-exposed group. Fasting serum samples were analyzed for PON1 activities towards substrates paraoxon, phenylacetate and diazoxon as well as for total cholesterol, triglycerides, HDL-C and LDL-C. The results showed a significantly lower diazoxonase activity (p 0.05) between the two groups. Our study suggested that the decreased PON1 activity among OPs exposed individuals cannot be linked to the atherosclerosis and CAD through the lipid profiles. A larger scale study is required to confirm our observation.
Paraoxonase
Phenylacetate
Aryldialkylphosphatase
Paraoxon
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Lipid Profile
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Introduction: Organophosphate (OP) is hydrolyzed by paraoxonase (PON1), an antioxidant enzyme that prevent atherosclerosis by inhibiting oxidative modification of low density lipoprotein (LDL). Low PON1 activities have been observed among individuals chronically exposed to OP while their decreased activities were reported in individuals with atherosclerosis related disease. However, a connection between chronic OP exposure, PON1 and the development of atherosclerosis has not yet been reported. The aim of this study was to investigate the effects of chronic OP exposure on the development of atherosclerosis in rat model. Materials & Methods: Twenty male Sprague-Dawley rats were divided into 3 groups; Group 1 did not receive any injection, both Group 2 and Group 3 received subcutaneous injection of vehicle and injection of 18.0 mg/kg of chlorpyrifos (CPF) respectively every other day for 180 days. Blood were analyzed for paraoxonase enzyme activities and ox-LDL. Aorta were harvested and stained for light and electron microscopic examination. Results: The paraoxonase activities, oxidized LDL and PON1: ox-LDL ratio were found to be significantly lower in OP exposed rats. The OP exposed rats also showed positive early atherosclerosis changes microscopically with VCAM-1 expression. The electron microscopic (EM) showed evidence of vascular damage with disruptions of the intimal layer of aorta, irregularly oriented and morphologically changed endothelial cells and numerous endothelial gaps with areas of deendothelialization. Discussion: This study highlighted that chronic OP exposure leads to the development of atherosclerosis which is confirmed microscopically and further affirmed by positive VCAM-1 expression. The basis for the above observation could be explain by low PON1 activities and low PON1:ox-LDL ratio. In conclusion, chronic intermittent low dose of OP chlorpyrifos induced the development of early atherosclerosis which could be explained by inability of the PON1 to hydrolyze oxidized-LDL.
Keywords: paraoxonase, atherosclerosis, chlorpyrifos, organophsphate, oxidized-low density lipoprotein
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Arylesterase
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Paraoxonase
Aryldialkylphosphatase
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Organophosphates (OPs) are commonly used as pesticides in agriculture. They are hydrolyzed by paraoxonase (PON1) which is a high density lipoprotein (HDL) associated enzyme known for its function to hydrolyze OPs into a relatively harmless substance. PON1 is also known to prevent atherosclerosis by hydrolyzing oxidized-low density lipoprotein (ox-LDL) as well as preventing the accumulation of lipid peroxides on LDL. Reports showed low PON1 activity among OPs-exposed individuals, while low PON1 activity was associated with a high risk of coronary artery disease (CAD). The link between chronic OPs exposure and lipid parameters which are known risk factors of CAD has not yet been reported. This study aimed at comparing the activities of PON1 and lipid parameters (ox-LDL, TC, TG, LDL-C and HDL-C) between workers who are exposed to OPs and non-exposed comparative groups. A cross sectional study was carried among 53 selected pesticides sprayers from 4 farms in Kuantan who fulfilled the criteria and 50 control subjects who were age, ethnicity and income bracket-matched. Fasting serum samples were analyzed for TC, TG, LDL-C and HDL-C (lipid profiles), ox-LDL and PON1 activities after the hydrolysis of substrates paraoxon, phenylacetate and diazoxon. Results showed a significantly lower (p 0.05) between the two groups. Our study suggested that OPs-exposed individuals might be predisposed to atherosclerosis and CAD through the decreased PON1 ability to hydrolyze ox-LDL but not through lipid profiles. A larger scale study is required to confirm our observation.
Paraoxonase
Aryldialkylphosphatase
Phenylacetate
Paraoxon
Arylesterase
Lipid Profile
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Background — Serum paraoxonase (PON1), an enzyme carried on HDL, inhibits LDL oxidation, and in human population studies, low PON1 activity is associated with atherosclerosis. In addition, PON1 knockout mice are more susceptible to lipoprotein oxidation and atherosclerosis. To evaluate whether PON1 protects against atherosclerosis and lipid oxidation in a dose-dependent manner, we generated and studied human PON1 transgenic mice. Methods and Results — Human PON1 transgenic mice were produced by using bacterial artificial chromosome genomic clones. The mice had 2- to 4-fold increased plasma PON1 levels, but plasma cholesterol levels were unchanged. Atherosclerotic lesions were significantly reduced in the transgenic mice when both dietary and apoE-null mouse models were used. HDL isolated from the transgenic mice also protected against LDL oxidation more effectively. Conclusions — Our results indicate that PON1 protects against atherosclerosis in a dose-dependent manner and suggest that it may be a potential target for developing therapeutic agents for the treatment of cardiovascular disease.
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Aryldialkylphosphatase
Apolipoprotein E
Knockout mouse
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