Relationship of Paraoxonase 1 (PON1) Gene Polymorphisms and Functional Activity With Systemic Oxidative Stress and Cardiovascular Risk

Bhattacharyya, Tamali; Nicholls, Stephen J.; Topol, Eric J.; Zhang, Renliang; Yang, Xia; Schmitt, David; Fu, Xiaoming; Shao, Mingyuan; Brennan, Danielle M.; Ellis, Stephen G.; Brennan, Marie Luise; Allayee, Hooman; Lusis, Aldons J.; Hazen, Stanley L.

doi:10.1001/jama.299.11.1265

Cited by 491 publications

(444 citation statements)

References 31 publications

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“…Studies of animal models [5][6][7] and in humans [8,9] are consistent with the hypothesis that PON1 decreases the risk of cardiovascular disease by lowering levels of oxidative stress, notably lipoprotein oxidation. In earlier studies, we proposed that HDL acquires PON1 by desorption from the hepatic cell membrane in a process probably mediated or facilitated by transient anchoring of HDL to the membrane [10].…”

supporting

confidence: 67%

HDL-associated paraoxonase-1 can redistribute to cell membranes and influence sensitivity to oxidative stress

Deakin

Bioletto

Bochaton‐Piallat

et al. 2011

Free Radical Biology and Medicine

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a b s t r a c t a r t i c l e i n f oParaoxonase-1 (PON1) is a high-density lipoprotein (HDL)-associated serum enzyme thought to make a major contribution to the antioxidant capacity of the lipoprotein. In previous studies, we proposed that HDL promoted PON1 secretion by transfer of the enzyme from its plasma membrane location to HDL transiently anchored to the hepatocyte. This study examined whether PON1 can be transferred into cell membranes and retain its enzymatic activities and functions. Using Chinese hamster ovary and human endothelial cells, we found that recombinant PON1 as well as PON1 associated with purified human HDL was freely exchanged between the external medium and the cell membranes. Transferred PON1 was located in the external face of the plasma membrane of the cells in an enzymatically active form. The transfer of PON1 led to a gain of function by the target cells, as revealed by significantly reduced susceptibility to oxidative stress and significantly increased ability to neutralize the bacterial virulence agent 3-oxo-C 12 -homoserine lactone. The data demonstrate that PON1 is not a fixed component of HDL and suggest that the enzyme could also exert its protective functions outside the lipoprotein environment. The observations may be of relevance to tissues exposed to oxidative stress and/or bacterial infection.

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supporting

confidence: 67%

HDL-associated paraoxonase-1 can redistribute to cell membranes and influence sensitivity to oxidative stress

Deakin

Bioletto

Bochaton‐Piallat

et al. 2011

Free Radical Biology and Medicine

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“…Alteration of enzyme activity due to polymorphisms in the PON genes may influence the development of atheromas and thus affect stroke risk [59] . Q192R, a common variant of the PON1 gene, is the major determinant of paraoxonase activity [60] . Several studies have shown that rare variants are associated with increased risk of ischemic stroke [61] and IMT [62] .…”

Section: Lipid Metabolismmentioning

confidence: 99%

Genetics of stroke

Guo

Liu

2010

Acta Pharmacol Sin

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Stroke is the second most common cause of death and the most common cause of disability in developed countries. Stroke is a multifactorial disease caused by a combination of environmental and genetic factors. Numerous epidemiologic studies have documented a significant genetic component in the occurrence of strokes. Genes encoding products involved in lipid metabolism, thrombosis, and inflammation are believed to be potential genetic factors for stroke. Although a large group of candidate genes have been studied, most of the epidemiological results are conflicting. Studies of stroke as a monogenic disease have made huge progress, and animal models serve as an indispensable tool to dissect the complex genetics of stroke. In the present review, we provide insight into the role of in vivo stroke models for the study of stroke genetics.

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“…Moreover, PON1 knockout mice display accelerated atherosclerosis progression and increased lipid oxidation [40,42,43]. Epidemiological studies indicate that high PON1 activity is inversely associated with the progression of atherosclerosis and reduction in the incidence of coronary artery disease [2,4,25,26,30,33]. Serum PON1 activity is influenced by environmental and genetic factors and varies among individuals in all populations.…”

Section: Introductionmentioning

confidence: 99%

Effect of atorvastatin on paraoxonase1 (PON1) and oxidative status

Nagila

Permpongpaiboon

Tantrarongroj

et al. 2009

Pharmacological Reports

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Abstract:It has been proposed that paraoxonase1 (PON1), a high density lipoprotein (HDL)-associated esterase/lactonase, has antiatherosclerotic properties. The activity of PON1 is influenced by PON1 polymorphisms. However, the influence of PON1 polymorphisms on PON1 activity and oxidative stress in response to lipid-lowering drugs remains poorly understood. The objective of the present study was to investigate the effects of atorvastatin on PON1 activity and oxidative status. The influence of PON1 polymorphisms on PON1 activity and oxidative status in response to atorvastatin treatment was also evaluated. In total, 22 hypercholesterolemic patients were treated with atorvastatin at a dose of 10 mg/day for 3 months. Lipid profile, lipid oxidation markers (malondialdehyde (MDA), conjugated diene (CD), total peroxides (TP)), total antioxidant substance (TAS), oxidative stress index (OSI), and paraoxonase1 activity were determined before and after treatment. L55M, Q192R, and T(-107)C PON1 polymorphisms were also determined. Atorvastatin treatment significantly reduced the levels of total cholesterol (24.5%), low density lipoprotein (LDL) cholesterol (25.4%), triglycerides (24.4%), CD (4.4%), MDA (15.2%), TP (13.0%) and OSI (24.0%), and significantly increased the levels of TAS (27.3%), and PON1 activity (14.0%). Interestingly, the increase in PON1 activity and the reduction in oxidative stress in response to atorvastatin were influenced only by the PON1 T-107C polymorphism. Atorvastatin treatment improved the lipid profile, lipid oxidation, and oxidative/antioxidative status markers including the activity of PON1 towards paraoxon. These beneficial effects may be attributed to the antioxidant properties of statins and the increase in PON1 activity. The increase in PON1 activity was enhanced by the PON1 T-107C polymorphism.

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Relationship of Paraoxonase 1 (PON1) Gene Polymorphisms and Functional Activity With Systemic Oxidative Stress and Cardiovascular Risk

Cited by 491 publications

References 31 publications

HDL-associated paraoxonase-1 can redistribute to cell membranes and influence sensitivity to oxidative stress

HDL-associated paraoxonase-1 can redistribute to cell membranes and influence sensitivity to oxidative stress

Genetics of stroke

Effect of atorvastatin on paraoxonase1 (PON1) and oxidative status

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