Skip to main content
SpringerLink
Log in

The paraoxonase gene family and atherosclerosis

  • Published:
Current Atherosclerosis Reports Aims and scope Submit manuscript

Abstract

Management of serum low-density lipoprotein has been a cornerstone of cardiovascular medicine for the past two decades. More recently, the attention paid to the protective role of high-density lipoprotein (HDL) in atherosclerosis has increased substantially, particularly with respect to the antioxidant properties of HDL. Considerable evidence supports the notion that the paraoxonase gene family is largely responsible for the antioxidant properties of HDL. This article reviews the three known members of the paraoxonase family and the evidence that supports their likely role in the development and progression of atherosclerosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

  1. Rosamond W, Flegal K, Furie K, et al.: Disease and Stroke Statistics—2008 Update: A Report From the American Heart Association Statistics. Circulation 2008 (in press).

  2. Gordon DJ, Probstfield JL, Garrison RJ, et al.: High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies. Circulation 1989, 79:8–15.

    CAS  PubMed  Google Scholar 

  3. Gotto AM, Brinton EA: Assessing low levels of high-density lipoprotein cholesterol as a risk factor in coronary heart disease: a working group report and update. J Am Coll Cardiol 2004, 43:717–724.

    Article  CAS  PubMed  Google Scholar 

  4. Sacks FM, Tonkin AM, Craven T, et al.: Coronary heart disease in patients with low LDL-cholesterol: benefit of pravastatin in diabetics and enhanced role for HDLcholesterol and triglycerides as risk factors. Circulation 2002, 105:1424–1428.

    Article  CAS  PubMed  Google Scholar 

  5. Barter P, Gotto AM, LaRosa JC, et al.: HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med 2007, 357:1301–1310.

    Article  CAS  PubMed  Google Scholar 

  6. Glueck CJ, Gartside P, Fallat RW, et al.: Longevity syndromes: familial hypobeta and familial hyperalpha lipoproteinemia. J Lab Clin Med 1976, 88:941–957.

    CAS  PubMed  Google Scholar 

  7. Brewer HB: Increasing HDL cholesterol levels. N Engl J Med 2004, 350:1491–1494.

    Article  CAS  PubMed  Google Scholar 

  8. Ameli S, Hultgardh-Nilsson A, Cercek B, et al.: Recombinant apolipoprotein A-I Milano reduces intimal thickening after balloon injury in hypercholesterolemic rabbits. Circulation 1994, 90:1935–1941.

    CAS  PubMed  Google Scholar 

  9. Nissen SE, Tsunoda T, Tuzcu EM, et al.: Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. JAMA 2003, 290:2292–2300.

    Article  CAS  PubMed  Google Scholar 

  10. Chiesa G, Monteggia E, Marchesi M, et al.: Recombinant apolipoprotein A-I(Milano) infusion into rabbit carotid artery rapidly removes lipid from fatty streaks. Circ Res 2002, 90:974–980.

    Article  CAS  PubMed  Google Scholar 

  11. Franceschini G, Sirtori CR, Capurso A, et al.: A-IMilano apoprotein. Decreased high density lipoprotein cholesterol levels with significant lipoprotein modifications and without clinical atherosclerosis in an Italian family. J Clin Invest 1980, 66:892–900.

    Article  CAS  PubMed  Google Scholar 

  12. Barter PJ, Caulfield M, Eriksson M, et al.: Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 2007, 357:2109–2122.

    Article  CAS  PubMed  Google Scholar 

  13. Nissen SE, Tardif JC, Nicholls SJ, et al.: Effect of torcetrapib on the progression of coronary atherosclerosis. N Engl J Med 2007, 356:1304–1316.

    Article  CAS  PubMed  Google Scholar 

  14. Tanne JH: Pfizer stops clinical trials of heart drug. BMJ 2006, 333:1237.

    Article  PubMed  Google Scholar 

  15. Libby P, Ridker PM, Maseri A: Inflammation and atherosclerosis. Circulation 2002, 105:1135–1143.

    Article  CAS  PubMed  Google Scholar 

  16. Navab M, Ananthramaiah GM, Reddy ST, et al.: The oxidation hypothesis of atherogenesis: the role of oxidized phospholipids and HDL. J Lipid Res 2004, 45:993–1007.

    Article  CAS  PubMed  Google Scholar 

  17. Maier JA, Barenghi L, Pagani F, et al.: The protective role of high-density lipoprotein on oxidized-low-density-lipoprotein-induced U937/endothelial cell interactions. Eur J Biochem 1994, 221:35–41.

    Article  CAS  PubMed  Google Scholar 

  18. Parthasarathy S, Barnett J, Fong LG: High-density lipoprotein inhibits the oxidative modification of low-density lipoprotein. Biochim Biophys Acta 1990, 1044:275–283.

    CAS  PubMed  Google Scholar 

  19. Navab M, Hama-Levy S, Van Lenten BJ, et al.: Mildly oxidized LDL induces an increased apolipoprotein J/paraoxonase ratio. J Clin Invest 1997, 99:2005–2019.

    Article  CAS  PubMed  Google Scholar 

  20. Mackness MI, Abbott C, Arrol S, Durrington PN: The role of high-density lipoprotein and lipid-soluble antioxidant vitamins in inhibiting low-density lipoprotein oxidation. Biochem J 1993, 294:829–834.

    CAS  PubMed  Google Scholar 

  21. Navab M, Imes SS, Hama SY, et al.: 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 1991, 88:2039–2046.

    Article  CAS  PubMed  Google Scholar 

  22. Hessler JR, Robertson AL, Chisolm GM: LDL-induced cytotoxicity and its inhibition by HDL in human vascular smooth muscle and endothelial cells in culture. Atherosclerosis 1979, 32:213–229.

    Article  CAS  PubMed  Google Scholar 

  23. Primo-Parmo SL, Sorenson RC, Teiber J, La Du BN: The human serum paraoxonase/arylesterase gene (PON1) is one member of a multigene family. Genomics 1996, 33:498–507.

    Article  CAS  PubMed  Google Scholar 

  24. Costa LG, Li WF, Richter RJ, et al.: The role of paraoxonase (PON1) in the detoxication of organophosphates and its human polymorphism. Chem Biol Interact 1999, 120:429–438.

    Article  Google Scholar 

  25. Ng CJ, Wadleigh DJ, Gangopadhyay A, et al.: Paraoxonase-2 is a ubiquitously expressed protein with antioxidant properties and is capable of preventing cell-mediated oxidative modification of low density lipoprotein. J Biol Chem 2001, 276:44444–44449.

    Article  CAS  PubMed  Google Scholar 

  26. Reddy ST, Wadleigh DJ, Grijalva VR, et al.: Human paraoxonase-3 is an HDL-associated enzyme with biological activity similar to paraoxonase-1 protein but is not regulated by oxidized lipids. Arterioscler Thromb Vasc Biol 2001, 21:542–547.

    CAS  PubMed  Google Scholar 

  27. Mackness MI, Mackness B, Durrington PN, et al.: Paraoxonase: biochemistry, genetics and relationship to plasma lipoproteins. Curr Opin Lipidol 1996, 7:69–76.

    Article  CAS  PubMed  Google Scholar 

  28. Watson AD, Navab M, Hama SY, et al.: Effect of platelet activating factor-acetylhydrolase on the formation and action of minimally oxidized low density lipoprotein. J Clin Invest 1995, 95:774–782.

    Article  CAS  PubMed  Google Scholar 

  29. Aviram M, Rosenblat M, Bisgaier CL, et al.: Paraoxonase inhibits high-density lipoprotein oxidation and preserves its functions. A possible peroxidative role for paraoxonase. J Clin Invest 1998, 101:1581–1590.

    Article  CAS  PubMed  Google Scholar 

  30. Feingold KR, Memon RA, Moser AH, Grunfeld C: Paraoxonase activity in the serum and hepatic mRNA levels decrease during the acute phase response. Atherosclerosis 1998, 139:307–315.

    Article  CAS  PubMed  Google Scholar 

  31. Shih DM, Gu L, Hama SY, et al.: Genetic-dietary regulation of serum paraoxonase expression and its role in atherogenesis in a mouse model. J Clin Invest 1996, 97:1630–1639.

    Article  CAS  PubMed  Google Scholar 

  32. Shih DM, Xia YR, Wang XP, et al.: Combined serum paraoxonase knockout/apolipoprotein E knockout mice exhibit increased lipoprotein oxidation and atherosclerosis. J Biol Chem 2000, 275:17527–17535.

    Article  CAS  PubMed  Google Scholar 

  33. Shih DM, Gu L, Xia YR, et al.: Mice lacking serum paraoxonase are susceptible to organophosphate toxicity and atherosclerosis. Nature 1998, 394:284–287.

    Article  CAS  PubMed  Google Scholar 

  34. Oda MN, Bielicki JK, Ho TT, et al.: Paraoxonase 1 overexpression in mice and its effect on high-density lipoproteins. Biochem Biophys Res Commun 2002, 290:921–927.

    Article  CAS  PubMed  Google Scholar 

  35. Tward A, Xia YR, Wang XP, et al.: Decreased atherosclerotic lesion formation in human serum paraoxonase transgenic mice. Circulation 2002, 106:484–490.

    Article  CAS  PubMed  Google Scholar 

  36. de Roos NM, Schouten EG, Scheek LM, et al.: Replacement of dietary saturated fat with trans fat reduces serum paraoxonase activity in healthy men and women. Metab Clin Exp 2002, 51:1534–1537.

    PubMed  Google Scholar 

  37. Senti M, Tomás M, Anglada R, et al.: Interrelationship of smoking, paraoxonase activity, and leisure time physical activity: a population-based study. Eur J Intern Med 2003, 14:178–184.

    Article  CAS  PubMed  Google Scholar 

  38. Sutherland WH, Walker RJ, de Jong SA, et al.: Reduced postprandial serum paraoxonase activity after a meal rich in used cooking fat. Arterioscler Thromb Vasc Biol 1999, 19:1340–1347.

    CAS  PubMed  Google Scholar 

  39. Jarvik GP, Tsai NT, McKinstry LA, et al.: Vitamin C and E intake is associated with increased paraoxonase activity. Arterioscler Thromb Vasc Biol 2002, 22:1329–1333.

    Article  CAS  PubMed  Google Scholar 

  40. Tomás M, Sentí M, García-Faria F, et al.: Effect of simvastatin therapy on paraoxonase activity and related lipoproteins in familial hypercholesterolemic patients. Arterioscler Thromb Vasc Biol 2000, 20:2113–2119.

    PubMed  Google Scholar 

  41. Draganov DI, La Du BN: Pharmacogenetics of paraoxonases: a brief review. Arch Pharmacol 2004, 369:78–88.

    Article  CAS  Google Scholar 

  42. Rosenblat M, Draganov D, Watson CE, et al.: Mouse macrophage paraoxonase 2 activity is increased whereas cellular paraoxonase 3 activity is decreased under oxidative stress. Arterioscler Thromb Vasc Biol 2003, 23:468–474.

    Article  CAS  PubMed  Google Scholar 

  43. Rosenblat M, Hayek T, Hussein K, Aviram M: Decreased macrophage paraoxonase 2 expression in patients with hypercholesterolemia is the result of their increased cellular cholesterol content: effect of atorvastatin therapy. Arterioscler Thromb Vasc Biol 2004, 24:175–180.

    Article  CAS  PubMed  Google Scholar 

  44. Draganov DI, Stetson PL, Watson CE, et al.: 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  PubMed  Google Scholar 

  45. Seo D, Goldschmidt-Clermont P, West M: Of mice and men: sparse statistical modeling in cardiovascular genomics. Ann Appl Statist 2007, 1:152–178.

    Article  Google Scholar 

  46. La Du BN, Adkins S, Kuo CL, Lipsig D: Studies on human serum paraoxonase/arylesterase. Chem Biol Interact 1993, 87:25–34.

    Article  PubMed  Google Scholar 

  47. Brophy VH, Jampsa RL, Clendenning JB, et al.: Effects of 5′ regulatory-region polymorphisms on paraoxonase-gene (PON1) expression. Am J Hum Genet 2001, 68:1428–1436.

    Article  CAS  PubMed  Google Scholar 

  48. Brophy VH, Hastings MD, Clendenning JB, et al.: Polymorphisms in the human paraoxonase (PON1) promoter. Pharmacogenetics 2001, 11:77–84.

    Article  CAS  PubMed  Google Scholar 

  49. James RW, Leviev I, Ruiz J, et al.: Promoter polymorphism T(-107)C of the paraoxonase PON1 gene is a risk factor for coronary heart disease in type 2 diabetic patients. Diabetes 2000, 49:1390–1393.

    Article  CAS  PubMed  Google Scholar 

  50. Leviev I, James RW: Promoter polymorphisms of human paraoxonase PON1 gene and serum paraoxonase activities and concentrations. Arterioscler Thromb Vasc Biol 2000, 20:516–521.

    CAS  PubMed  Google Scholar 

  51. Hu Y, Tian H, Liu R: Gln-Arg192 polymorphism of paraoxonase 1 is associated with carotid intima-media thickness in patients of type 2 diabetes mellitus of Chinese. Diabetes Res Clin Pract 2003, 61:21–27.

    Article  CAS  PubMed  Google Scholar 

  52. Akhmedova S, Anisimov S, Yakimovsky A, Schwartz E: Gln → Arg 191 polymorphism of paraoxonase and Parkinson’s disease. Hum Hered 1999, 49:178–180.

    Article  CAS  PubMed  Google Scholar 

  53. Kondo I, Yamamoto M: Genetic polymorphism of paraoxonase 1 (PON1) and susceptibility to Parkinson’s disease. Brain Res 1998, 806:271–273.

    Article  CAS  PubMed  Google Scholar 

  54. Mackness MI, Arrol S, Mackness B, Durrington PN: Alloenzymes of paraoxonase and effectiveness of high-density lipoproteins in protecting low-density lipoprotein against lipid peroxidation. Lancet 1997, 349:851–852.

    Article  CAS  PubMed  Google Scholar 

  55. Wheeler JG, Keavney BD, Watkins H, et al.: Four paraoxonase gene polymorphisms in 11212 cases of coronary heart disease and 12786 controls: meta-analysis of 43 studies. Lancet 2004, 363:689–695.

    Article  CAS  PubMed  Google Scholar 

  56. Fong CS, Cheng CW, Wu RM: Pesticides exposure and genetic polymorphism of paraoxonase in the susceptibility of Parkinson’s disease. Acta Neurol (Taiwan) 2005, 14:55–60.

    Google Scholar 

  57. Mackness B, Mackness MI, Arrol S, et al.: Effect of the molecular polymorphisms of human paraoxonase (PON1) on the rate of hydrolysis of paraoxon. Br J Pharmacol 1997, 122:265–268.

    Article  CAS  PubMed  Google Scholar 

  58. Slowik A, Wloch D, Szermer P, et al.: Paraoxonase 2 gene C311S polymorphism is associated with a risk of large vessel disease stroke in a Polish population. Cerebrovasc Dis 2007, 23:395–400.

    Article  CAS  PubMed  Google Scholar 

  59. Sanghera DK, Aston CE, Saha N, Kamboh MI: DNA polymorphisms in two paraoxonase genes (PON1 and PON2) are associated with the risk of coronary heart disease. Am J Hum Genet 1998, 62:36–44.

    Article  CAS  PubMed  Google Scholar 

  60. Chen Q, Reis SE, Kammerer CM, et al.: Association between the severity of angiographic coronary artery disease and paraoxonase gene polymorphisms in the National Heart, Lung, and Blood Institute-sponsored Women’s Ischemia Syndrome Evaluation (WISE) study. Am J Hum Genet 2003, 72:13–22.

    Article  CAS  PubMed  Google Scholar 

  61. Campo S, Sardo AM, Campo GM, et al.: Identification of paraoxonase 3 gene (PON3) missense mutations in a population of southern Italy. Mutat Res 2004, 546:75–80.

    CAS  PubMed  Google Scholar 

  62. Sanghera DK, Manzi S, Minster RL, et al.: Genetic variation in the paraoxonase-3 (PON3) gene is associated with serum PON1 activity. Ann Hum Genet 2008, 72:72–81.

    Article  CAS  PubMed  Google Scholar 

  63. Ozaki K, Tanaka T: Genome-wide association study to identify SNPs conferring risk of myocardial infarction and their functional analyses. Cell Mol Life Sci 2005, 62:1804–1813.

    Article  CAS  PubMed  Google Scholar 

  64. Helgadottir A, Thorleifsson G, Manolescu A: A common variant on chromosome 9p21 affects the risk of myocardial infarction. Science 2007, 316:1491–1493.

    Article  CAS  PubMed  Google Scholar 

  65. McPherson R, Pertsemlidis A, Kavaslar N, Stewart A: A common allele on chromosome 9 associated with coronary heart disease. Science 2007, 316:1488–1491.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. University of Miami Miller School of Medicine, 1120 NW 14th Street, Miami, FL, 33136, USA

    David Seo

Authors
  1. David Seo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pascal Goldschmidt-Clermont
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David Seo.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Seo, D., Goldschmidt-Clermont, P. The paraoxonase gene family and atherosclerosis. Curr Atheroscler Rep 11, 182–187 (2009). https://doi.org/10.1007/s11883-009-0029-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11883-009-0029-3

Keywords

Search

Navigation