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Mice lacking serum paraoxonase are susceptible to organophosphate toxicity and atherosclerosis

Author

Listed:
  • Diana M. Shih

    (47-123 CHS, UCLA School of Medicine
    Molecular Biology Institute, UCLA)

  • Lingjie Gu

    (47-123 CHS, UCLA School of Medicine
    Molecular Biology Institute, UCLA)

  • Yu-Rong Xia

    (47-123 CHS, UCLA School of Medicine
    Molecular Biology Institute, UCLA)

  • Mohamad Navab

    (47-123 CHS, UCLA School of Medicine)

  • Wan-Fen Li

    (University of Washington)

  • Susan Hama

    (47-123 CHS, UCLA School of Medicine)

  • Lawrence W. Castellani

    (47-123 CHS, UCLA School of Medicine
    Molecular Biology Institute, UCLA)

  • Clement E. Furlong

    (University of Washington)

  • Lucio G. Costa

    (University of Washington)

  • Alan M. Fogelman

    (47-123 CHS, UCLA School of Medicine)

  • Aldons J. Lusis

    (47-123 CHS, UCLA School of Medicine
    Molecular Biology Institute, UCLA)

Abstract

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 chlorpyrifos1,2,3. PON1 may also confer protection against coronary artery disease by destroying pro-inflammatory oxidized lipids present in oxidized low-density lipoproteins (LDLs)4,5,6,7,8. 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.

Suggested Citation

  • Diana M. Shih & Lingjie Gu & Yu-Rong Xia & Mohamad Navab & Wan-Fen Li & Susan Hama & Lawrence W. Castellani & Clement E. Furlong & Lucio G. Costa & Alan M. Fogelman & Aldons J. Lusis, 1998. "Mice lacking serum paraoxonase are susceptible to organophosphate toxicity and atherosclerosis," Nature, Nature, vol. 394(6690), pages 284-287, July.
    • Handle: RePEc:nat:nature:v:394:y:1998:i:6690:d:10.1038_28406
    DOI: 10.1038/28406
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    Cited by:

    1. Dominika Kunachowicz & Milena Ściskalska & Marta Kepinska, 2023. "Modulatory Effect of Lifestyle-Related, Environmental and Genetic Factors on Paraoxonase-1 Activity: A Review," IJERPH, MDPI, vol. 20(4), pages 1-36, February.
    2. Ines Potočnjak & Vesna Degoricija & Matias Trbušić & Sanda Dokoza Terešak & Bojana Radulović & Gudrun Pregartner & Andrea Berghold & Beate Tiran & Gunther Marsche & Saša Frank, 2016. "Metrics of High-Density Lipoprotein Function and Hospital Mortality in Acute Heart Failure Patients," PLOS ONE, Public Library of Science, vol. 11(6), pages 1-11, June.
    3. Lin Wang & Xi Zhang & Chenwang Tang & Pengcheng Li & Runtao Zhu & Jing Sun & Yunfeng Zhang & Hua Cui & Jiajia Ma & Xinyu Song & Weiwen Zhang & Xiang Gao & Xiaozhou Luo & Lingchong You & Ye Chen & Zhuo, 2022. "Engineering consortia by polymeric microbial swarmbots," Nature Communications, Nature, vol. 13(1), pages 1-13, December.

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