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Studies on protective effects of human paraoxonases 1 and 3 on atherosclerosis in apolipoprotein E knockout mice

Gene Therapy volume 17, pages 626–633 (2010)Cite this article

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Abstract

Paraoxonase (PON) possesses antiatherogenic potentials, but the distinct functions of PON members in alleviating atherosclerosis are not yet clear. This study aimed to evaluate the protective effects of hPON1 and hPON3 against atherosclerosis, and thereby exploring their synergistic mechanism in atherosclerosis development. We generated the recombinant adenovirus AdPON1 and AdPON3, which were capable of expressing hPON1 and hPON3. After AdPON1 and AdPON3 were injected intravenously into 5-week-old apolipoprotein E knockout mice, abundant hPON1 and hPON3 mRNA expression levels were detected. However, increase in serum lactonase activity was detected only in AdPON1-treated mice. Serum antioxidation and anti-inflammation capabilities in AdPON1-treated mice, reflected by malondialdehyde, total antioxidant capability and tumor necrosis factor-α levels, were greatly enhanced, whereas those in AdPON3-treated mice were not significantly affected. Nevertheless, histological analysis revealed that adenovirus-mediated expression of hPON1, hPON3 or both of them reduced atherosclerotic plaque area to a similar extent. Although no synergistic mechanism was detected in reducing arterial lesion size, hPON1 and hPON3 showed synergistic effects on promoting macrophage cholesterol efflux. In conclusion, hPON1 and hPON3 exhibited similar potentials in reducing arterial lesion size, but they exerted antiatherogenic effects in distinct ways.

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References

  1. Kleemann R, Zadelaar S, Kooistra T . Cytokines and atherosclerosis: a comprehensive review of studies in mice. Cardiovasc Res 2008; 79: 360–376.

    Article  CAS  Google Scholar 

  2. Lusis AJ . Atherosclerosis. Nature 2000; 407: 233–241.

    Article  CAS  Google Scholar 

  3. Aviram M, Rosenblat M . Paraoxonases 1, 2, and 3, oxidative stress, and macrophage foam cell formation during atherosclerosis development. Free Radic Biol Med 2004; 37: 1304–1316.

    Article  CAS  Google Scholar 

  4. Shih DM, Xia YR, Wang XP, Miller E, Castellani LW, Subbanagounder G et al. Combined serum paraoxonase knockout/apolipoprotein E knockout mice exhibit increased lipoprotein oxidation and atherosclerosis. J Biol Chem 2000; 276: 17527–17535.

    Article  Google Scholar 

  5. Harel M, Aharoni A, Gaidukov L, Brumshtein B, Khersonsky O, Meged R et al. Structure and evolution of the serum paraoxonase family of detoxifying and anti-atherosclerotic enzymes. Nat Struct Mol Biol 2004; 11: 412–419.

    Article  CAS  Google Scholar 

  6. Draganov DI, Stetson PL, Watson CE, Billecke SS, La Du BN . Rabbit serum paraoxonase 3(PON3) is a high density lipoprotein-associated lactonase and protects low density lipoprotein against oxidation. J Biol Chem 2000; 275: 33435–33442.

    Article  CAS  Google Scholar 

  7. Mackness B, Durrington PN, McElduff P, Yarnell J, Azam N, Watt M et al. Low paraoxonase activity predicts coronary events in the Caerphilly Prospective Study. Circulation 2003; 107: 2775–2779.

    Article  CAS  Google Scholar 

  8. Shih DM, Gu L, Xia YR, Navab M, Li WF, Hama S et al. Mice lacking serum paraoxonase are susceptible to organophosphate toxicity and atherosclerosis. Nature 1998; 394: 284–287.

    Article  CAS  Google Scholar 

  9. Tward A, Xia YR, Wang XP, Shi YS, Park C, Castellani LW et al. Decreased atherosclerotic lesion formation in human serum paraoxonase transgenic mice. Circulation 2002; 106: 484–490.

    Article  CAS  Google Scholar 

  10. Aviram M, Rosenblat M . Paraoxonases and cardiovascular diseases: pharmacological and nutritional influences. Curr Opin Lipidol 2005; 16: 393–399.

    Article  CAS  Google Scholar 

  11. Aviram M, Rosenblat M, Bisgaier CL, Newton RS, Primo-Parmo SL, La Du BN . Paraoxonase inhibits high density lipoprotein (HDL) oxidation and preserves its functions: a possible peroxidative role for paraoxonase. J Clin Invest 1998; 101: 1581–1590.

    Article  CAS  Google Scholar 

  12. Rozenberg O, Shih DM, Aviram M . Human serum paraoxonase (PON1) decreases macrophage cholesterol biosynthesis: a possible role for its phospholipase-A2 activity and lysophosphatidylcholine formation. Arterioscler Thromb Vasc Biol 2003; 23: 461–467.

    Article  CAS  Google Scholar 

  13. Ng CJ, Bourquard N, Hama SY, Shih D, Grijalva VR, Navab M et al. Adenovirus-mediated expression of human paraoxonase 3 protects against the progression of atherosclerosis in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 2007; 27: 1368–1374.

    Article  CAS  Google Scholar 

  14. Shih DM, Xia YR, Wang XP, Wang SS, Bourquard N, Fogelman AM et al. Decreased obesity and atherosclerosis in human paraoxonase 3 transgenic mice. Circ Res 2007; 100: 1200–1207.

    Article  CAS  Google Scholar 

  15. Ng CJ, Shih DM, Hama SY, Villa N, Navab M, Reddy ST . The paraoxonase gene family and atherosclerosis. Free Radic Biol Med 2005; 38: 153–163.

    Article  CAS  Google Scholar 

  16. Draganov DI, Teiber JF, Speelman A, Osawa Y, Sunahara R, La Du BN . Human paraoxonases (PON1, PON2, and PON3) are lactonases with overlapping and distinct substrate specificities. J Lipid Res 2005; 46: 1239–1247.

    Article  CAS  Google Scholar 

  17. Gaidukov L, Tawfik DS . High affinity, stability, and lactonase activity of serum paraoxonase PON1 anchored on HDL with ApoA-I. Biochemistry 2005; 44: 11843–11854.

    Article  CAS  Google Scholar 

  18. Berliner JA, Watson AD . A role for oxidized phospholipids in atherosclerosis. N Engl J Med 2005; 353: 9–11.

    Article  CAS  Google Scholar 

  19. Kirii H, Niwa T, Yamada Y, Wada H, Saito K, Iwakura Y et al. Lack of interleukin-1beta decreases the severity of atherosclerosis in ApoE-deficient mice. Arterioscler Thromb Vasc Biol 2003; 23: 656–660.

    Article  CAS  Google Scholar 

  20. Fazio S, Babaev VR, Murray AB, Hasty AH, Carter KJ, Gleaves LA et al. Increased atherogenesis in mice reconstituted with apolipoprotein E null macrophages. Proc Natl Acad Sci USA 1997; 94: 4647–4652.

    Article  CAS  Google Scholar 

  21. Wang N, Silver DL, Costet P, Tall AR . Specific binding of ApoA1, enhanced cholesterol efflux and altered plasma membrane morphology in cells expressing ABCA1. J Biol Chem 2000; 275: 33053–33058.

    Article  CAS  Google Scholar 

  22. Kennedy MA, Barrera GC, Nakamura K, Baldán A, Tarr P, Fishbein MC et al. ABCG1 has a critical role in mediating cholesterol efflux to HDL and preventing cellular lipid accumulation. Cell Metab 2005; 1: 121–131.

    Article  CAS  Google Scholar 

  23. Draganov DI . Human PON3, effects beyond the HDL. Circ Res 2007; 100: 1104–1105.

    Article  CAS  Google Scholar 

  24. Liu Y, Mackness B, Mackness M . Comparison of the ability of paraoxonases 1 and 3 to attenuate the in vitro oxidation of low-density lipoprotein and reduce macrophage oxidative stress. Free Radic Biol Med 2008; 45: 743–748.

    Article  CAS  Google Scholar 

  25. Mackness B, Quarck R, Verreth W, Mackness M, Holvoet P . Human paraoxonase-1 overexpression inhibits atherosclerosis in a mouse model of metabolic syndrome. Arterioscler Thromb Vasc Biol 2006; 26: 1545–1550.

    Article  CAS  Google Scholar 

  26. Khersonsky O, Tawfik DS . Structure-reactivity studies of serum paraoxonase PON1 suggest that its native activity is lactonase. Biochemistry 2005; 44: 6371–6382.

    Article  CAS  Google Scholar 

  27. Rosenblat M, Oren R, Aviram M . Lysophosphatidylcholine (LPC) attenuates macrophage mediated oxidation of LDL. Biochem Biophys Res Comm 2006; 344: 1271–1277.

    Article  CAS  Google Scholar 

  28. Canault M, Peiretti F, Mueller C, Kopp F, Morange P, Rihs S et al. Exclusive expression of transmembrane TNF-alpha in mice reduces the inflammatory response in early lipid lesions of aortic sinus. Atherosclerosis 2004; 172: 211–218.

    Article  CAS  Google Scholar 

  29. Ohta H, Wada H, Niwa T, Kirii H, Iwamoto N, Fujii H et al. Disruption of tumor. necrosis factor-alpha gene diminishes the development of atherosclerosis in ApoE-deficient mice. Atherosclerosis 2005; 180: 11–17.

    Article  CAS  Google Scholar 

  30. Lind L . Circulating markers of inflammation and atherosclerosis. Atherosclerosis 2003; 169: 203–214.

    Article  CAS  Google Scholar 

  31. Devlin CM, Kuriakose G, Hirsch E, Tabas I . Genetic alterations of IL-1 receptor antagonist in mice affect plasma cholesterol level and foam cell lesion size. Proc Natl Acad Sci USA 2002; 99: 6280–6285.

    Article  CAS  Google Scholar 

  32. Chi H, Messas E, Levine RA, Graves DT, Amar S . Interleukin-1 receptor signaling mediates atherosclerosis associated with bacterial exposure and/or a high-fat diet in a murine apolipoprotein E heterozygote model: pharmacotherapeutic implications. Circulation 2004; 110: 1678–1685.

    Article  CAS  Google Scholar 

  33. Rader DJ . Molecular regulation of HDL metabolism and function: implications for novel therapies. J Clin Invest 2006; 116: 90–100.

    Article  Google Scholar 

  34. Joy T, Hegele RA . Is raising HDL a futile strategy for atheroprotection? Nat Rev Drug Discov 2008; 7: 143–155.

    Article  CAS  Google Scholar 

  35. Guns PJ, Assche TV, Verreth W, Fransen P, Mackness B, Mackness M et al. Paraoxonase 1 gene transfer lowers vascular oxidative stress and improves vasomotor function in apolipoprotein E-deficient mice with pre-existing atherosclerosis. Brit J Pharmacol 2008; 153: 508–516.

    Article  CAS  Google Scholar 

  36. Lv HQ, Zhu J, Zang YH, Ze YG, Qin JC . Cloning, high level expression of human paraoxonase-3 in Sf9 cells and pharmacological characterization of its product. Biochem Pharmacol 2005; 70: 1019–1025.

    Article  Google Scholar 

  37. Van Eck M, Herijgers N, Van Dijk KW, Havekes LM, Hofker MH, Groot P et al. Effect of macrophage-derived mouse ApoE, human ApoE3-Leiden, and human ApoE2 (Arg1583Cys) on cholesterol levels and atherosclerosis in ApoE-deficient mice. Arterioscler Thromb Vasc Biol 2000; 20: 119–127.

    Article  CAS  Google Scholar 

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Acknowledgements

The study was supported by the National Natural Science foundation of China (Grant no. 30670858) to Junchuan Qin and Key Project of National Natural Science foundation of China (Grant no. 90713015) to Ju Huangxian.

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  1. C Zhang and W Peng: These authors contributed equally to this work.

Authors and Affiliations

  1. State Key Laboratory of Pharmaceutical Biotechnology, Life Science School, Nanjing University, Nanjing, PR China

    C Zhang, W Peng, J Zhu, Y Zang, J Zhang & J Qin

  2. Lab of Toxicology, Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, PR China

    M Wang & W Shi

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  1. C Zhang
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Correspondence to Y Zang or J Zhang.

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Zhang, C., Peng, W., Wang, M. et al. Studies on protective effects of human paraoxonases 1 and 3 on atherosclerosis in apolipoprotein E knockout mice. Gene Ther 17, 626–633 (2010). https://doi.org/10.1038/gt.2010.11

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