Mice lacking serum paraoxonase are susceptible to organophosphate toxicity and atherosclerosis

Shih, Diana M.; Gu, Lin; Xia, Yu; Navab, Mohamad; Li, Wan Fen; Hama, Susan; Castellani, Lawrence W.; Furlong, Clement E.; Costa, Lucio G.; Fogelman, Alan M.; Lusis, Aldons J.

doi:10.1038/28406

Cited by 1,013 publications

(770 citation statements)

References 15 publications

Supporting

Mentioning

739

Contrasting

Unclassified

Order By: Relevance

“…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: 68%

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

View full text Add to dashboard Cite

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.

show abstract

supporting

confidence: 68%

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

View full text Add to dashboard Cite

show abstract

“…The elevated oxidative stress burden in cardiovascular diseases may result in the formation of lipid peroxidation products in HDL, which in turn may negatively affect their beneficial features. In fact, HDL from mice lacking PON1 were unable to prevent the accumulation of lipid peroxides in LDL and these mice demonstrated an increased susceptibility to atherosclerosis, 144 while introduction of the human PON1 transgene in mice had opposite effects on the anti-oxidative functions of HDL and atherosclerosis. 145 Interestingly, if residing on the same HDL particle, PON1 and MPO were found to interact and reciprocally affect each other's enzymatic activity.…”

Section: Paraoxonase-1 and Lipid Peroxidation Productsmentioning

confidence: 99%

Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy

Annema

Eckardstein

2016

Translational Research

View full text Add to dashboard Cite

Low plasma levels of high-density lipoprotein (HDL) cholesterol are associated with increased risks of coronary heart disease. HDL mediates cholesterol efflux from macrophages for reverse transport to the liver and elicits many anti-inflammatory and anti-oxidative activities which are potentially antiatherogenic. Nevertheless, HDL has not been successfully targeted by drugs for prevention or treatment of cardiovascular diseases. One potential reason is the targeting of HDL cholesterol which does not capture the structural and functional complexity of HDL particles. Hundreds of lipid species and dozens of proteins as well as several microRNAs have been identified in HDL. This physiological heterogeneity is further increased in pathologic conditions due to additional quantitative and qualitative molecular changes of HDL components which have been associated with both loss of physiological function and gain of pathologic dysfunction. This structural and functional complexity of HDL has prevented clear assignments of molecules to the functions of normal HDL and dysfunctions of pathologic HDL. Systematic analyses of structure-function relationships of HDL-associated molecules and their modifications are needed to test the different components and functions of HDL for their relative contribution in the pathogenesis of atherosclerosis. The derived biomarkers and targets may eventually help to exploit HDL for treatment and diagnostics of cardiovascular diseases.

show abstract

“…Indeed, PON1 protects LDL particles against copper-induced lipid oxidation in vitro [3,28,29] and transgenic mice overexpressing the human PON1 gene have reduced atherosclerotic lesions [48]. 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].…”

Section: Introductionmentioning

confidence: 99%

Effect of atorvastatin on paraoxonase1 (PON1) and oxidative status

Nagila

Permpongpaiboon

Tantrarongroj

et al. 2009

Pharmacological Reports

View full text Add to dashboard Cite

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.

show abstract

Mice lacking serum paraoxonase are susceptible to organophosphate toxicity and atherosclerosis

Cited by 1,013 publications

References 15 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

Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy

Effect of atorvastatin on paraoxonase1 (PON1) and oxidative status

Contact Info

Product

Resources

About