Anti-Inflammatory Properties of Paraoxonase-1 in Atherosclerosis

  • Bharti MacknessEmail author
  • Mike Mackness
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 660)


Atherosclerosis is increasingly recognised as an inflammatory disease. The inflammatory process begins with the oxidation of low-density lipoprotein (LDL) in the artery wall. The ability of high-density lipoprotein (HDL) to inhibit the oxidation of LDL (and cell membranes) and promote macrophage cholesterol efflux through the action of several of its associated proteins, particularly paraoxonase-1 (PON1), reduces the inflammation associated with atherosclerosis. In vivo, in animal models, ablation of the PON1 gene is pro-inflammatory and pro-atherogenic, while overexpression of human PON1 is anti-inflammatory and anti-atherogenic. In subjects with diabetes mellitus, PON1 is dysfunctional due to glycation, reducing its ability to retard LDL and cell membrane oxidation and contributing to the inflammation typical of diabetes, leading to the excess atherosclerosis common in this disease.


Paraoxonase-1 High-density lipoprotein Inflammation Oxidation Lipid hydroperoxides Paraoxonase-3 


  1. Ansell, B.J., Fonarow, G.C., Fogelman, A.M. (2007) The paradox of dysfunctional high-density lipoprotein. Curr Opin Lipidol 18: 427–434.CrossRefPubMedGoogle Scholar
  2. Ansell, B.J., Navab, M., Hama, S., Kamranpour, N., Fonarow, G., Hough, G. et al. (2003) Inflammatory/antiinflammatory properties of high-density lipoprotein distinguish patients from control subjects better than high-density lipoprotein cholesterol levels and are favourably affected by simvastatin treatment. Circulation 108: 2751–2756.CrossRefPubMedGoogle Scholar
  3. Arrol, S., Mackness, M.I., Durrington, P.N. (1996) High-density lipoprotein associated enzymes and the prevention of low-density lipoprotein oxidation. Eur J Lab Med 4: 33–38.Google Scholar
  4. Aviram, M., Billecke, S., Sorenson, R., Bisgaier, C., Newton, R., Rosenblat, M., Erogul, J., Hsu, C., Dunlop, C., La Du, B.N (1998) Paraoxonase active site required for protection against LDL oxidation involves its free sulphydryl group and is different from that required for its arylesterase/paraoxonase activities: selective action of human paraoxonase alloenzymes Q and R. Arterioscl Thromb Vasc Biol 10: 1617–1624.Google Scholar
  5. Aviram, M., Rosenblat, M. (2004) Paraoxonases 1, 2, and 3, oxidative stress, and macrophage foam cell formation during atherosclerosis development. Free Radic Biol Med 37: 1304–16.CrossRefPubMedGoogle Scholar
  6. Feingold, K.R., Memon, R.A., Moser, A.H., Grunfeld, C. (1998) Paraoxonase activity in the serum and hepatic mRNA levels decrease during the acute phase response. Atherosclerosis 139: 307–315.CrossRefPubMedGoogle Scholar
  7. Ferretti, G., Bacchetti, T., Busni, D., Rabini, R.A., Curatola, G. (2004) Protective effect of paraoxonase activity in high-density lipoproteins against erythrocyte membranes peroxidation: a comparison between healthy subjects and type 1 diabetic patients. J Clin Endocrinol Metab 89: 2957–2962.CrossRefPubMedGoogle Scholar
  8. Liu, Y., Mackness, B., Mackness, M., (2008) 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 45:743–748Google Scholar
  9. Lusis, A.J. (2000) Atherosclerosis. Nature 407: 233–241.CrossRefPubMedGoogle Scholar
  10. Mackness, B., Mackness, M. (2009) HDL - Why all the fuss? Ann Clin Biochem- 46:5–7Google Scholar
  11. Mackness, B., Hine, D., Liu, Y. Mastorikou, M., Mackness, M. (2004) Paraoxonase 1 inhibits oxidised LDL-induced MCP-1 production by endothelial cells. BBRC 318: 680–683.PubMedGoogle Scholar
  12. Mackness, B., Hine, D., McElduff, P., Mackness, M. (2006) High C-reactive protein and low paraoxonase 1 in diabetes as risk factors for coronary heart disease. Atherosclerosis 185: 396–401.CrossRefGoogle Scholar
  13. Mackness, B., Hunt, R., Durrington, P.N., Mackness, M.I. (1997) Increased immunolocalisation of paraoxonase, clusterin and apolipoprotein AI in the human artery wall with progression of atherosclerosis. Arterioscler Thromb Vasc Biol 17: 1233–1238.PubMedGoogle Scholar
  14. Mackness, B., Quarck, R., Verreth, W., Mackness, M., Holvoet, P. (2006a) Human paraoxonase-1 overexpression inhibits atherosclerosis in a mouse model of metabolic syndrome. Arterioscler Thromb Vasc Biol 26:1545–1550.CrossRefPubMedGoogle Scholar
  15. Mackness, M.I., Arrol, S. & Durrington, P.N. (1991) Paraoxonase prevents accumulation of lipoperoxides in low-density lipoprotein. FEBS Letts 286: 152–154.CrossRefGoogle Scholar
  16. Mackness, MI., Durrington, PN., Mackness, B. (2002) The role of paraoxonase in lipid metabolism. In: Costa, LG., Furlong, CE (eds.). Paraoxonase (PON1) in health and disease. Norwell, MA: Kluwer.Google Scholar
  17. Marathe, G.K., Zimmerman, G.A., McIntyre, T.M. (2003) Platelet-activating factor acetylhydrolase, and not paraoxonase-1, is the oxidized phospholipid hydrolase of high density lipoprotein particles. J Biol Chem 278: 3937–3947.CrossRefPubMedGoogle Scholar
  18. Marsillach, J., Mackness, B., Mackness, M., Riu, F., Beltran, R., Joven, J., Camps, J. (2008) Immunohistochemical analysis of paraoxonases- 1, 2, and 3 expression in normal mouse tissues. Free Rad Biol Med 45: 146–157.CrossRefPubMedGoogle Scholar
  19. Mastorikou, M., Mackness, B., Liu, Y., Mackness, M. (2008) Glycation of paraoxonase-1 inhibits its activity and impairs the ability of high-density lipoprotein to metabolise membrane lipid hydroperoxides. Diabetic Med 25: 1049–1055.CrossRefPubMedGoogle Scholar
  20. Mastorikou, M., Mackness, M., Mackness, B. (2006) Defective metabolism of oxidised-phospholipid by high-density lipoprotein from people with type 2 diabetes. Diabetes 55: 3099–3103.CrossRefPubMedGoogle Scholar
  21. Miller G.J., Miller N.E. (1975) Plasma high-density lipoprotein concentration and the development of ischaemic heart disease. Lancet 1: 16–19.CrossRefPubMedGoogle Scholar
  22. Navab, M., Imes, S.S., Hama, S.Y., Hough, G.P., Ross, L.A., Bork, R.W., Valente, A.J., Berliner, J.A., Drinkwater, D.C., Laks, H. & Fogelman, A.M. (1991) Monocyte transmigration induced by modification of low density lipoprotein in cocultures of human aortic wall cells is due to induction of monocyte chemotactic protein 1 synthesis and is abolished by high density lipoprotein. J Clin Invest 88: 2039–2046.CrossRefPubMedGoogle Scholar
  23. Nicholls, S.J., Dusting, G.J., Cutri, B. Bao, S., Drummond, G.R., Rye K-A., Barter, P.J. (2005) Reconstituted high-density lipoproteins inhibit the acute pro-oxidant and proinflammatory vascular changes induced by periarterial collar in normocholesterolemic rabbits. Circulation 111: 1543–1550.CrossRefPubMedGoogle Scholar
  24. Rodrigo, L., Mackness, B., Durrington, P.N., Hernandez, A., Mackness, M.I. (2001) Hydrolysis of platelet-activating factor by human serum paraoxonase. Biochem J 354: 1–7.CrossRefPubMedGoogle Scholar
  25. Ross, R. (1993) The pathogenesis of atherosclerosis: a perspective for the 1990’s. Nature 362: 801–809.CrossRefPubMedGoogle Scholar
  26. Shih, D.M., Gu, L., Xia Y-R., Navab, M., Li, W-F., Hama, S., Castellani, L.W., Furlong, C.E., Costa, L.G., Fogelman, A.M., Lusis, A.J. (1998) Mice lacking serum paraoxonase are susceptible to organophosphate toxicity and atherosclerosis. Nature 394: 284–287.CrossRefPubMedGoogle Scholar
  27. Steinberg, D., Parthasarathy, S., Carew, T.E., Khoo, J.C. and Witztum, J.L. (1989) Beyond cholesterol modifications of low-density lipoprotein that increase its atherogenicity. New Engl J Med 320: 915–924.CrossRefPubMedGoogle Scholar
  28. Watson, A.D., Berliner, J.A., Hama, S.Y., La Du, B.N., Fault, K.F., Fogelman, A.M., Navab, M. (1995)Protective effect of high density lipoprotein associated paraoxonase - Inhibition of the biological activity of minimally oxidised low-density lipoprotein. J Clin Invest 96: 2882–2891.CrossRefPubMedGoogle Scholar

Copyright information

© Humana Press, a part of Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Universitat Rovari i Virgili, Center de Recerca Biomedica Hospital Universitari de Sant JoanReusSpain

Personalised recommendations