Paraoxonase-1: Characteristics and Role in Atherosclerosis and Carotid Artery Disease

Author(s): S. Lioudaki*, C. Verikokos, G. Kouraklis, C. Ioannou, E. Chatziioannou, D. Perrea, C. Klonaris.

Journal Name: Current Vascular Pharmacology

Volume 17 , Issue 2 , 2019

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Graphical Abstract:


Paraoxonase-1 (PON-1) is a calcium-dependent enzyme that is synthesized in the liver and then secreted in blood where it is bound to high density lipoprotein (HDL). PON-1 is a hydrolase with a wide range of substrates, including lipid peroxides. It is considered responsible for many of the antiatherogenic properties of HDL. PON-1 prevents low density lipoprotein (LDL) oxidation, a process that is considered to contribute to the initiation and development of atherosclerosis. PON-1 activity and levels are influenced by gene polymorphisms; of the 2 common variants, one is in position 192 (Q192R) and one in position 55 (M55L). Also, many drugs affect PON-1 activity. The role of PON-1 in carotid atherosclerosis is inconsistent. Some studies show an association of PON-1 polymorphisms with carotid plaque formation, whereas others do not. The aim of this review is to summarize the characteristics of PON-1, its interactions with drugs and its role in atherosclerosis and especially its relationship with carotid artery disease.

Keywords: Paraoxonase, polymorphisms, atherosclerosis, carotid, oxidative stress, drugs.

Louridas G, Junaid A. Management of carotid artery stenosis. Update for family physicians. Can Fam Physician 2005; 51: 984-9.
Johnson BH, Bonafede MM, Watson C. Short- and longer-term health-care resource utilization and costs associated with acute ischemic stroke. Clinicoecon Outcomes Res 2016; 8: 53-61.
Bousser MG. Stroke prevention: An update. Front Med 2012; 6: 22-34.
Cohen E, Aviram M, Khatib S, et al. Increased levels of human carotid lesion linoleic acid hydroperoxide in symptomatic and asymptomatic patients is inversely correlated with serum HDL and paraoxonase 1 activity. J Lipids 2012; 2012: 762560.
Grady PA. Pathophysiology of extracranial cerebral arterial stenosis-a critical review. Stroke 1984; 15: 224-36.
Hollander M, Bots ML, Del Sol AI, et al. Carotid plaques increase the risk of stroke and subtypes of cerebral infarction in asymptomatic elderly: The Rotterdam study. Circulation 2002; 105: 2872-7.
Katakami N, Saito M, Kaneto H, et al. Combined effect of oxidative stress-related gene polymorphisms on the progression of carotid atherosclerosis in Japanese type 2 diabetes. Atherosclerosis 2009; 207: 29-31.
Back M, Weber C, Lutgens E. Regulation of atherosclerotic plaque inflammation. J Intern Med 2015; 278: 462-82.
Tavori H, Vaya J, Aviram M. Paraoxonase 1 attenuates human plaque atherogenicity: Relevance to the enzyme lactonase activity. Adv Exp Med Biol 2010; 660: 99-111.
Tavori H, Aviram M, Khatib S, et al. Human carotid atherosclerotic plaque increases oxidative state of macrophages and low-density lipoproteins, whereas paraoxonase 1 (PON-1) decreases such atherogenic effects. Free Radic Biol Med 2009; 46: 607-15.
Tavori H, Aviram M, Khatib S, et al. Paraoxonase 1 protects macrophages from atherogenicity of a specific triglyceride isolated from human carotid lesion. Free Radic Biol Med 2011; 51: 234-42.
Stocker R, Keaney JF. Role of oxidative modifications in atherosclerosis. Physiol Rev 2004; 84: 1381-478.
Durrington PN, Mackness M, Mackness MI. Paraoxonase and atherosclerosis. Arterioscler Thromb Vasc Biol 2001; 21: 473-80.
Aviram M, Vaya J. Paraoxonase 1 activities, regulation, and interactions with atherosclerotic lesion. Curr Opin Lipidol 2013; 24: 339-44.
Deakin SP, James RW. Genetic and environmental factors modulating serum concentrations and activities of the antioxidant enzyme paraoxonase-1. Clin Sci (Lond) 2004; 107: 435-47.
Efrat M, Aviram M. Paraoxonase 1 interactions with HDL, antioxidants and macrophages regulate atherogenesis - a protective role for HDL phospholipids. Adv Exp Med Biol 2010; 660: 153-66.
Schmidt H, Schmidt R, Niederkorn K, et al. Paraoxonase PON1 polymorphism leu-Met54 is associated with carotid atherosclerosis: Results of the Austrian stroke prevention study. Stroke 1998; 29: 2043-8.
Mackness B, Durrington P, McElduff P, et al. Low paraoxonase activity predicts coronary events in the Caerphilly prospective study. Circulation 2003; 107: 2775-9.
Rozenberg O, Rosenblat M, Coleman R, Shih DM, Aviram M. Paraoxonase (PON-1) deficiency is associated with increased macrophage oxidative stress: Studies in PON-1-knockout mice. Free Radic Biol Med 2003; 34: 774-84.
Shih DM, Gu L, Xia YR. Mice lacking serum paraoxonase are susceptible to organophosphate toxicity and atherosclerosis. Nature 1998; 394: 284-7.
Shih DM, Xia YR, Wang XP. Combined serum paraoxonase knockout/apolipoprotein E knockout mice exhibit increased lipoprotein oxidation and atherosclerosis. J Biol Chem 2000; 275: 17527-35.
Tward A, Xia YR, Wang XP. Decreased atherosclerotic lesion formation in human serum paraoxonase transgenic mice. Circulation 2002; 106: 484-90.
Gupta N, Gill K, Singh S. Paraoxonases: Structure, gene polymorphism and role in coronary artery disease. Indian J Med Res 2009; 130: 361-8.
Cosan D, Colak E, Saydam F, et al. Associationof paraoxonase 1 (PON-1) gene polymorphisms and concentration with essential hypertension. J Clin Expertl Hypertens 2016; 38: 602-7.
Ayub A, Mackness MI, Arrol S, Mackness B, Patel J, Durrington PN. Serum paraoxonase after myocardial infarction. Arterioscler Thromb Vasc Biol 1999; 19: 330-5.
Gnasso A, Motti C, Irace C, et al. The Arg allele in position 192 of PON-1 is associated with carotid atherosclerosis in subjects with elevated HDLs. Atherosclerosis 2002; 164: 289-95.
Souza-Nogueira A, Camargo AE, Remondi FA. atherogenicity and the Framingham risk score. Arch Endocrinol Metab 2016; 60: 426-35.
Tomas M, Senti M, Garcia-Faria F, et al. Effect of Simvastatin therapy on Paraoxonase activity and related lipoproteins in Familial Hypercholesterolemic patients. Thromb Vasc Biol 2000; 20: 2113-9.
Nagila A, Permpongpaiboon T, Tantrarongroj S, et al. Effect of atorvastatin on paraoxonase 1 (PON1) and oxidative status. Pharmacol Rep 2009; 61: 892-8.
Mirdamadi H, Sztanek F, Derdak Z, Seres I, Harangi M, Paragh G. The human paraoxonase-1 phenotype modifies the effect of statins on paraoxonase activity and lipid parameters. Br J Clin Pharmacol 2008; 66: 366-74.
Leviev I, James R. Simvastatin increases plasma levels of the antioxidantenzyme paraoxonase by PON1 gene activation. Atherosclerosis 2000; 151: 41.
Abdin AA, Hassanien MA, Ibrahim EA, Abou El-Noeman S-D. Modulating effect of atorvastatin on paraoxonase 1 activity in type 2 diabetic Egyptian patients with or without nephropathy. J Diabetes Compl 2010; 24: 325-33.
Isgor MM, Beydemir S. Some cardiovascular therapeutics inhibit paraoxonase 1 (PON1) from human serum. Eur J Pharmacol 2010; 645: 135-42.
Ekinci D, Beydemir S. Effect of some analgesics on paraoxonase-1 purified from human serum. J Enzyme Inhib Med Chem 2009; 24: 1034-9.
Ekinci D, Beydemir S. Evaluation of the impacts of antibiotic drugs on PON 1; A major bio scavenger against cardiovascular diseases. Eur J Pharmacol 2009; 617: 84-9.
Turkes C, Beydemir S. Human serum paraoxonase-1 (hPON1): In vitro inhibition effects of moxifloxacin hydrochloride, levofloxacin hemihidrate, cefepime hydrochloride, cefotaxime sodium and ceftizoxime sodium. J Enzyme Inhib Med Chem 2015; 30: 622-8.
Alim Z, Beydemir S. Some anticancer agents act on human serum paraoxonase-1 to reduce its activity. Chem Biol Drug Des 2016; 88: 188-96.
Saadaoui MH, Hellara I, Neffati F, et al. In vitro effects of three antidepressant drugs on plasma paraoxonase activity. Drug Metabol Drug Interact 2012; 27: 209-15.
Harangi M, Seres I, Varga Z, et al. Atorvastatin effect on high-density lipoprotein-associated paraoxonase activity and oxidative DNA damage. Eur J Clin Pharmacol 2004; 60: 685-91.
Kassai A, Illyes L, Mirdamadi H, et al. The effect of atorvastatin therapy on lecithin: Cholesterol acyltransferase, cholesteryl ester transfer protein and the antioxidant paraoxonase. Clin Biochem 2007; 40: 1-5.
Guo Y, Wang C, Cao J, et al. Antioxidant and lipid-regulating effects of probucol combined with atorvastatin in patients with acute coronary syndrome. J Thorac Dis 2015; 7: 368-75.
Derosa G, Mugellini A, Pesce RM, D’Angelo A, Maffioli P. Olmesartan combined with amlodipine on oxidative stress parameters in type 2 diabetics, compared with single therapies. Medicine 2016; 95: e3084.
Fortunato G, Rubba P, Panico S, et al. A paraoxonase gene polymorphism, PON 1 (55), as an independent risk factor for increased carotid intima-media thickness in middle-aged women. Atherosclerosis 2003; 167: 141-8.
Cao H, Girard-Globa A, Serusclat A, et al. Lack of association between carotid intima-media thickness and paraoxonase gene polymorphism in non-insulin dependent diabetes mellitus. Atherosclerosis 1998; 138: 361-6.
Dessi M, Gnasso A, Motti C, et al. Influence of the human paraoxonase polymorphism (PON-1 192) on the carotid-wall thickening in a healthy population. Coron Artery Dis 1999; 10: 595-9.
Scherrer DZ, Zago VH, Vieira IC, et al. Q192R SNP of PON1 seems not to be associated with carotid atherosclerosis risk factors in an asymptomatic and normolipidemic Brazilian population sample. Arq Bras Cardiol 2015; 105: 45-52.
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: 21-7.
Burdon KP, Langefeld CD, Beck SR. Association of genes of lipid metabolism with measures of subclinical cardiovascular disease in the Diabetes Heart Study. J Med Genet 2005; 42: 720-4.
Wang M, Lang X, Zou L, Huang S, Xu Z. Four genetic polymorphisms of paraoxonase gene and risk of coronary heart disease: A meta-analysis based on 88 case-control studies. Atherosclerosis 2011; 214: 377-85.
Chen H, Ding S, Zhou M, et al. PON1 L55M and Q192R gene polymorphisms and CAD risks in patients with hyperlipidemia: Clinical study of possible associations. Herz 2018; 43(7): 642-8.
Shenhar-Tsarfaty S, Waiskopf N, Ofek K, et al. Atherosclerosis and arteriosclerosis parameters in stroke patients associate with paraoxonase polymorphism and esterase activities. Eur J Neurol 2013; 20: 891-8.
Leus FR, Wittekoek ME, Prins J, Kastelein JJ, Voorbij HA. Paraoxonase gene polymorphisms are associated with carotid arterial wall thickness in subjects with familial hypercholesterolemia. Atherosclerosis 2000; 149: 371-7.
Jarvik GP, Rozek LS, Brophy VH, et al. Paraoxonase (PON-1) phenotype is a better predictor of vascular disease than is PON-1(192) or PON-1(55) genotype. Arterioscler Thromb Vasc Biol 2000; 20: 2441-7.
Giannopoulos A, Kakkos S, Abbott A, et al. Long-term mortality in patients with asymptomatic carotid stenosis: Implications for statin therapy. Eur J Vasc Endovasc Surg 2015; 50: 573-82.
Otocka-Kmiecik A, Mikhailidis DP, Nicholls SJ, Davidson M, Rysz J, Banach M. Dysfunctional HDL: A novel important diagnostic and therapeutic target in cardiovascular disease? Prog Lipid Res 2012; 51: 314-24.
Charles-Schoeman C, Lee YY, Shahbazian A, et al. Association of Paraoxonase 1 gene polymorphism and enzyme activity with carotid plaque in rheumatoid arthritis. Arthritis Rheum 2013; 65: 2765-72.
Han L, Xu XJ, Liang XH, Ma J. Association of paraoxonase polymorphisms with carotid artery atherosclerosis in essential hypertension patients. Genet Mol Res 2013; 12: 5174-85.
Mete R, Oran M, Alpsoy S, et al. Carotid intima-media thickness and serum paraoxonase-1 activity in patients with Helicobacter pylori. Eur Rev Med Pharmacol Sci 2013; 17: 2884-9.
Arslan A, Tuzun FA, Arslan H, et al. The relationship between serum paraoxonase levels and carotid atherosclerotic plaque formation in Alzheimer’s patients. Neurol Neurochir Pol 2016; 50: 403-9.

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Article Details

Year: 2019
Page: [141 - 146]
Pages: 6
DOI: 10.2174/1570161115666171129212359
Price: $65

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