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Oxidative Stress and Inflammation in Non-communicable Diseases - Molecular Mechanisms and Perspectives in Therapeutics pp 33–41Cite as

Inflammation, Infection, Cancer and All That…The Role of Paraoxonases

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Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 824))

Abstract

The paraoxonase (PON) gene family consists of three members, PON1, PON2 and PON3. All PON proteins possess antioxidant properties and lipo-lactonase activities, and are implicated in the pathogenesis of several inflammatory diseases including atherosclerosis, Alzheimer’s, Parkinson’s, diabetes and cancer. Despite the role of PON proteins in critical cellular functions and associated pathologies, the physiological substrates and molecular mechanisms by which PON proteins function as anti-inflammatory proteins remain largely unknown. PON1 is found exclusively extracellular and associated solely with high-density lipoprotein (HDL) particles in the circulation, and, in part, confers the anti-oxidant and anti-inflammatory properties associated with HDL. Recent studies demonstrated that the intracellular PON proteins; PON2 and PON3 (i) are associated with mitochondria and mitochondria-associated membranes, (ii) modulate mitochondria-dependent superoxide production, and (iii) prevent apoptosis. Overexpression of PON2 and PON3 genes protected (i) mitochondria from antimycin or oligomycin mediated mitochondrial dysfunction and (ii) ER stress and ER stress mediated mitochondrial dysfunction. These studies illustrate that the anti-inflammatory effects of PON2 and PON3 may, in part, be mediated by their role in mitochondrial and associated organelle function. Since oxidative stress as a result of mitochondrial dysfunction is implicated in the development of inflammatory diseases including atherosclerosis and cancer, these recent studies on PON2 and PON3 proteins may provide a mechanism for the scores of epidemiological studies that show a link between PON genes and numerous inflammatory diseases. Understanding such mechanisms will provide novel routes of intervention in the treatment of diseases associated with pro-inflammatory oxidative stress.

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References

  1. Reddy ST, Devarajan A, Bourquard N, Shih D, Fogelman AM. Is it just paraoxonase 1 or are other members of the paraoxonase gene family implicated in atherosclerosis? Curr Opin Lipidol. 2008;19:405–8.

    Article  CAS  PubMed  Google Scholar 

  2. She ZG, Chen HZ, Yan Y, Li H, Liu DP. The human paraoxonase gene cluster as a target in the treatment of atherosclerosis. Antioxid Redox Signal. 2012;16:597–632.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. 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 

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

    Article  CAS  PubMed  Google Scholar 

  5. Aldridge WN. Serum esterases I. Two types of esterase (A and B) hydrolysing p-nitrophenyl acetate, propionate and butyrate and a method for their determination. Biochem J. 1953;53:110–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  6. Aldridge WN. Serum esterases II. An enzyme hydrolyzing diethyl p-nitrophenyl acetate (E600) and its identity with the A-esterase of mammalian sera. Biochem J. 1953;53:117–24.

    CAS  PubMed Central  PubMed  Google Scholar 

  7. Bhattacharyya T, Nicholls SJ, Topol EJ, Zhang R, Yang X, Schmitt D, et al. Relationship of paraoxonase 1 (PON1) gene polymorphisms and functional activity with systemic oxidative stress and cardiovascular risk. JAMA. 2008;299:1265–76.

    Article  CAS  PubMed  Google Scholar 

  8. Stevens RC, Suzuki SM, Cole TB, Park SS, Richter RJ, Furlong CE. Engineered recombinant human paraoxonase 1 purified from Escherichia coli protects against organophosphate poisoning. Proc Natl Acad Sci U S A. 2008;105:12780–4.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Stoltz DA, Ozer EA, Taft PJ, Barry M, Liu L, Kiss PJ, et al. Drosophila are protected from Pseudomonas aeruginosa lethality by transgenic expression of paraoxonase-1. J Clin Invest. 2008;118:3123–31.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Witte I, Altenhöfer S, Wilgenbus P, Amort J, Clement AM, Pautz A, et al. Beyond reduction of atherosclerosis: PON2 provides apoptosis resistance and stabilizes tumor cells. Cell Death Dis. 2011;13(2):e112.

    Article  Google Scholar 

  11. Schweikert EM, Devarajan A, Witte I, Wilgenbus P, Amort J, Förstermann U, et al. PON3 is upregulated in cancer tissues and protects against mitochondrial superoxide-mediated cell death. Cell Death Differ. 2012;19:1549–60.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. 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;394:284–7.

    Article  CAS  PubMed  Google Scholar 

  13. 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;275:17527–35.

    Article  CAS  PubMed  Google Scholar 

  14. 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;106:484–90.

    Article  CAS  PubMed  Google Scholar 

  15. Devarajan A, Bourquard N, Hama S, Navab M, Grijalva VR, Morvardi S, et al. Paraoxonase 2 deficiency alters mitochondrial function and exacerbates the development of atherosclerosis. Antioxid Redox Signal. 2011;14:341–51.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. 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;100:1200–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. She ZG, Zheng W, Wei YS, Chen HZ, Wang AB, Li HL, et al. Human paraoxonase gene cluster transgenic overexpression represses atherogenesis and promotes atherosclerotic plaque stability in ApoE-null mice. Circ Res. 2009;104:1160–8.

    Article  CAS  PubMed  Google Scholar 

  18. Aviram M, Rosenblat M, Bisgaier CL, Newton RS, Primo-Parmo SL, La Du BN. Paraoxonase inhibits high-density lipoprotein oxidation and preserves its functions. A possible peroxidative role for paraoxonase. J Clin Invest. 1998;101:1581–90.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Watson AD, Berliner JA, Hama SY, La Du BN, Faull KF, Fogelman AM, et al. Protective effect of high density lipoprotein associated paraoxonase. Inhibition of the biological activity of minimally oxidized low density lipoprotein. J Clin Invest. 1995;96:2882–91.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Deakin SP, Bioletto S, Bochaton-Piallat ML, James RW. HDL-associated PON1 can redistribute to cell membranes and influence sensitivity to oxidative stress. Free Radic Biol Med. 2011;50:102–9.

    Article  CAS  PubMed  Google Scholar 

  21. Aviram M. Atherosclerosis: cell biology and lipoproteins – paraoxonases protect against atherosclerosis and diabetes development. Curr Opin Lipidol. 2012;23:169–71.

    Article  CAS  PubMed  Google Scholar 

  22. Kim DS, Marsillach J, Furlong CE, Jarvik GP. Pharmacogenetics of paraoxonase activity: elucidating the role of high-density lipoprotein in disease. Pharmacogenomics. 2013;14:1495–515.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Huang Y, Wu Z, Riwanto M, Gao S, Levison BS, Gu X, et al. Myeloperoxidase, paraoxonase-1, and HDL form a functional ternary complex. J Clin Invest. 2013;123:3815–28.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Mackness M, Mackness B. Targeting paraoxonase-1 in atherosclerosis. Expert Opin Ther Targets. 2013;17:829–37.

    Article  CAS  PubMed  Google Scholar 

  25. Tang WH, Hartiala J, Fan Y, Wu Y, Stewart AF, Erdmann J, et al. Clinical and genetic association of serum paraoxonase and arylesterase activities with cardiovascular risk. Arterioscler Thromb Vasc Biol. 2012;32:2803–12.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Charles-Schoeman C, Lee YY, Shahbazian A, Gorn AH, Fitzgerald J, Ranganath VK, et al. Association of paraoxonase 1 gene polymorphisms and enzyme activity with carotid plaque in rheumatoid arthritis. Arthritis Rheum. 2013;65:2765–72.

    Article  CAS  PubMed  Google Scholar 

  27. Garcia-Heredia A, Marsillach J, Rull A, Triguero I, Fort I, Mackness B, et al. Paraoxonase-1 inhibits oxidized low-density lipoprotein-induced metabolic alterations and apoptosis in endothelial cells: a non directed metabolomic study. Mediat Inflamm. 2013;2013:156053.

    Google Scholar 

  28. Garcia-Heredia A, Kensicki E, Mohney RP, Rull A, Triguero I, Marsillach J, et al. Paraoxonase-1 deficiency is associated with severe liver steatosis in mice fed a high-fat high-cholesterol diet: a metabolomic approach. J Proteome Res. 2013;12:1946–55.

    Article  CAS  PubMed  Google Scholar 

  29. Jarvik GP, Rozek LS, Brophy VH, Hatsukami TS, Richter RJ, Schellenberg GD, et al. Paraoxonase (PON1) phenotype is a better predictor of vascular disease than is PON1(192) or PON1(55) genotype. Arterioscler Thromb Vasc Biol. 2000;120:2441–7.

    Article  Google Scholar 

  30. Mackness B, Durrington P, McElduff P, Yarnell J, Azam N, Watt M, et al. Low paraoxonase activity predicts coronary events in the Caerphilly Prospective Study. Circulation. 2003;107:2775–9.

    Article  CAS  PubMed  Google Scholar 

  31. Tang WH, Wu Y, Mann S, Pepoy M, Shrestha K, Borowski AG, et al. Diminished antioxidant activity of high-density lipoprotein-associated proteins in systolic heart failure. Circ Heart Fail. 2011;4:59–64.

    Article  CAS  PubMed  Google Scholar 

  32. Aviram M, Vaya J. Paraoxonase 1 activities, regulation, and interactions with atherosclerotic lesion. Curr Opin Lipidol. 2013;24:339–44.

    Article  CAS  PubMed  Google Scholar 

  33. Besler C, Heinrich K, Rohrer L, Doerries C, Riwanto M, Shih DM, et al. Mechanisms underlying adverse effects of HDL on eNOS-activating pathways in patients with coronary artery disease. J Clin Invest. 2011;121:2693–708.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Hazen SL, Heinecke JW. 3-Chlorotyrosine, a specific marker of myeloperoxidase-catalyzed oxidation, is markedly elevated in low density lipoprotein isolated from human atherosclerotic intima. J Clin Invest. 1997;99:2075–81.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Zhang R, Brennan ML, Shen Z, MacPherson JC, Schmitt D, Molenda CE, et al. Myeloperoxidase functions as a major enzymatic catalyst for initiation of lipid peroxidation at sites of inflammation. J Biol Chem. 2002;277:46116–22.

    Article  CAS  PubMed  Google Scholar 

  36. Ng CJ, Bourquard N, Grijalva V, Hama S, Shih DM, Navab M, et al. Paraoxonase-2 deficiency aggravates atherosclerosis in mice despite lower apolipoprotein-B-containing lipoproteins: anti-atherogenic role for paraoxonase-2. J Biol Chem. 2006;281:29491–500.

    Article  CAS  PubMed  Google Scholar 

  37. Mabile L, Meilhac O, Escargueil-Blanc I, Troly M, Pieraggi MT, Salvayre R, et al. Mitochondrial function is involved in LDL oxidation mediated by human cultured endothelial cells. Arterioscler Thromb Vasc Biol. 1997;17:1575–82.

    Article  CAS  PubMed  Google Scholar 

  38. Altenhöfer S, Witte I, Teiber JF, Wilgenbus P, Pautz A, Li H, et al. One enzyme, two functions: PON2 prevents mitochondrial superoxide formation and apoptosis independent from its lactonase activity. J Biol Chem. 2010;6(285):24398–403.

    Article  Google Scholar 

  39. Ng CJ, Wadleigh DJ, Gangopadhyay A, Hama S, Grijalva VR, Navab M, 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;276:44444–9.

    Article  CAS  PubMed  Google Scholar 

  40. Ohnishi T, Trumpower BL. Differential effects of antimycin on ubisemiquinone bound in different environments in isolated succinate. Cytochrome c reductase complex. J Biol Chem. 1980;255:3278–84.

    CAS  PubMed  Google Scholar 

  41. Kim SB, Berdanier CD. Oligomycin sensitivity of mitochondrial F(1)F(0)-ATPase in diabetes-prone BHE/Cdb rats. Am J Physiol. 1999;277:E702–7.

    CAS  PubMed  Google Scholar 

  42. Horke S, Witte I, Wilgenbus P, Krüger M, Strand D, Förstermann U. Paraoxonase-2 reduces oxidative stress in vascular cells and decreases endoplasmic reticulum stress-induced caspase activation. Circulation. 2007;17(115):2055–64.

    Article  Google Scholar 

  43. Horke S, Witte I, Wilgenbus P, Altenhöfer S, Krüger M, Li H, et al. Protective effect of paraoxonase-2 against endoplasmic reticulum stress-induced apoptosis is lost upon disturbance of calcium homoeostasis. Biochem J. 2008;416:395–405.

    Article  CAS  PubMed  Google Scholar 

  44. Devarajan A, Grijalva VR, Bourquard N, Meriwether 3rd D, Imaizumi S, Shin BC, et al. Macrophage paraoxonase 2 regulates calcium homeostasis and cell survival under endoplasmic reticulum stress conditions and is sufficient to prevent the development of aggravated atherosclerosis in paraoxonase 2 deficiency/apoE(−/−) mice on a western diet. Mol Genet Metab. 2012;107:416–27.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  45. Shih DM, Xia YR, Yu JM, Lusis AJ. Temporal and tissue-specific patterns of PON3 expression in mouse: in situ hybridization analysis. Adv Exp Med Biol. 2009;660:73–87.

    Article  Google Scholar 

  46. Reddy ST, Wadleigh DJ, Grijalva V, Ng C, Hama S, Gangopadhyay A, 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;21:542–7.

    Article  CAS  PubMed  Google Scholar 

  47. Draganov DI. Lactonases with organophosphatase activity: structural and evolutionary perspectives. Chem Biol Interact. 2010;187:370–2.

    Article  CAS  PubMed  Google Scholar 

  48. 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;46:1239–47.

    Article  CAS  PubMed  Google Scholar 

  49. Shiner EK, Rumbaugh KP, Williams SC. Interkingdom signaling: deciphering the language of acyl homoserine lactones. FEMS Microbiol Rev. 2005;29:935–47.

    Article  CAS  PubMed  Google Scholar 

  50. Chun CK, Ozer EA, Welsh MJ, Zabner M, Greenberg EP. Inactivation of a Pseudomonas aeruginosa quorum-sensing signal by human airway epithelia. Proc Natl Acad Sci U S A. 2004;101:3587–90.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  51. Stoltz DA, Ozer EA, Ng CJ, Yu JM, Reddy ST, Lusis A, et al. Paraoxonase-2 deficiency enhances Pseudomonas aeruginosa quorum sensing in murine tracheal epithelia. Am J Physiol Lung Cell Mol Physiol. 2007;292:L852–60.

    Article  CAS  PubMed  Google Scholar 

  52. Devarajan A, Bourquard N, Grijalva VR, Gao F, Ganapathy E, Verma J, et al. Role of PON2 in innate immune response in an acute infection model. Mol Genet Metab. 2013;110:362–70.

    Article  CAS  PubMed  Google Scholar 

  53. Kim JB, Xia YR, Romanoski CE, Lee S, Meng Y, Shi YS, et al. Paraoxonase-2 modulates stress response of endothelial cells to oxidized phospholipids and a bacterial quorum-sensing molecule. Arterioscler Thromb Vasc Biol. 2011;31:2624–33.

    Article  PubMed Central  PubMed  Google Scholar 

  54. Schweikert EM, Amort J, Wilgenbus P, Förstermann U, Teiber JF, Horke S. Paraoxonases-2 and -3 are important defense enzymes against Pseudomonas aeruginosa virulence factors due to their anti-oxidative and anti-inflammatory properties. J Lipids. 2012;2012:352857.

    Google Scholar 

  55. Witte I, Foerstermann U, Devarajan A, Reddy ST, Horke S. Protectors or traitors: the roles of PON2 and PON3 in atherosclerosis and cancer. J Lipids. 2012;2012:342806.

    Google Scholar 

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, 90095, Los Angeles, CA, USA

    Asokan Devarajan

  2. Department of Medicine, David Geffen School of Medicine at UCLA, 90095, Los Angeles, CA, USA

    Diana Shih

  3. Department of Obstetrics and Gynecology Department of Molecular and Medical Pharmacology Division of Cardiology, Department of Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, 951679, 90095-1679, 43–144 CHS, Los Angeles, CA, 167917, USA

    Srinivasa T. Reddy

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  1. Asokan Devarajan
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  2. Diana Shih
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  3. Srinivasa T. Reddy
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Correspondence to Srinivasa T. Reddy .

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Editors and Affiliations

  1. Hospital Universitari de Sant Joan, IISPV, URV, Unitat de Recerca Biomèdica, Reus, Spain

    Jordi Camps

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Devarajan, A., Shih, D., Reddy, S.T. (2014). Inflammation, Infection, Cancer and All That…The Role of Paraoxonases. In: Camps, J. (eds) Oxidative Stress and Inflammation in Non-communicable Diseases - Molecular Mechanisms and Perspectives in Therapeutics. Advances in Experimental Medicine and Biology, vol 824. Springer, Cham. https://doi.org/10.1007/978-3-319-07320-0_5

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