Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:542-547
© 2001 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Human Paraoxonase-3 Is an HDL-Associated Enzyme With Biological Activity Similar to Paraoxonase-1 Protein but Is Not Regulated by Oxidized Lipids
From the Atherosclerosis Research Unit, Division of Cardiology, Department of Medicine (S.T.R., D.J.W., V.G., C.N., S.M., D.M.S., A.J.L., M.N., A.M.F.), the Department of Molecular and Medical Pharmacology (S.T.R.), and the Department of Microbiology, Immunology and Molecular Genetics (A.J.L.), University of California, Los Angeles, and the School of Medicine (A.G.), Vanderbilt University, Nashville, Tenn.
Correspondence to Srinivasa T. Reddy, PhD, Department of Medicine, and Department of Molecular and Medical Pharmacology, University of California, Los Angeles, 650 Charles E. Young Drive South, A8-131 CHS, Los Angeles, CA 90095. E-mail sreddy{at}mednet.ucla.edu
Abstract—Paraoxonase-1
(PON1) is a secreted protein associated primarily with high density
lipoprotein (HDL) and participates in the prevention of low density
lipoprotein (LDL) oxidation. Two other paraoxonase (PON) family
members, namely, PON2 and PON3, have been identified. In this study, we
report the cloning and characterization of the human PON3 gene from
HepG2 cells. Tissue Northern analysis identifies an 
1.3-kb
transcript for PON3 primarily in the liver. PON3-specific peptide
antibodies detect an 40-kDa protein associated with HDL and absent
from LDL. Pretreatment of cultured human aortic
endothelial cells with supernatants from HeLa Tet On
cell lines overexpressing PON3 prevents the formation of mildly
oxidized LDL and inactivates preformed mildly oxidized LDL.
In contrast to PON1, PON3 is not active against the synthetic
substrates paraoxon and phenylacetate. Furthermore, PON3 expression is
not regulated in HepG2 cells by oxidized phospholipids and is not
regulated in the livers of mice fed a high-fat atherogenic
diet.
Key Words: paraoxonase • MM-LDL • PON3 • atherosclerosis • oxidized lipids
This article has been cited by other articles:
 |
|
 |
|
  M. Cesari, E. Marzetti, A. Laudisio, L. Antonica, M. Pahor, R. Bernabei, and G. Zuccala Interaction of HDL cholesterol concentrations on the relationship between physical function and inflammation in community-dwelling older persons Age Ageing, November 5, 2009; (2009) afp194v1. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Romani, G. E. De Medio, S. di Tullio, R. Lapalombella, I. Pirisinu, V. Margonato, A. Veicsteinas, M. Marini, and G. Rosi Modulation of paraoxonase 1 and 3 expression after moderate exercise training in the rat J. Lipid Res., October 1, 2009; 50(10): 2036 - 2045. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Y. Fujimoto, J. P. Kane, B. Y. Ishida, M. S. Bloom, and R. W. Browne High-density lipoprotein metabolism and the human embryo Hum. Reprod. Update, August 28, 2009; (2009) dmp029v2. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z.-G. She, W. Zheng, Y.-S. Wei, H.-Z. Chen, A.-B. Wang, H.-L. Li, G. Liu, R. Zhang, J.-J. Liu, W. B. Stallcup, et al. Human Paraoxonase Gene Cluster Transgenic Overexpression Represses Atherogenesis and Promotes Atherosclerotic Plaque Stability in ApoE-Null Mice Circ. Res., May 22, 2009; 104(10): 1160 - 1168. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Sattler and B. Levkau Sphingosine-1-phosphate as a mediator of high-density lipoprotein effects in cardiovascular protection Cardiovasc Res, May 1, 2009; 82(2): 201 - 211. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. J. Richter, G. P. Jarvik, and C. E. Furlong Determination of Paraoxonase 1 Status Without the Use of Toxic Organophosphate Substrates Circ Cardiovasc Genet, December 1, 2008; 1(2): 147 - 152. [Full Text] [PDF]
|
|
|
|
 |
|
 D J Hausenloy and D M Yellon Targeting residual cardiovascular risk: raising high-density lipoprotein cholesterol levels Postgrad. Med. J., November 1, 2008; 84(997): 590 - 598. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R.W. Browne, W.B. Shelly, M.S. Bloom, A.J. Ocque, J.R. Sandler, H.G. Huddleston, and V.Y. Fujimoto Distributions of high-density lipoprotein particle components in human follicular fluid and sera and their associations with embryo morphology parameters during IVF Hum. Reprod., August 1, 2008; 23(8): 1884 - 1894. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. F. Teiber, S. Horke, D. C. Haines, P. K. Chowdhary, J. Xiao, G. L. Kramer, R. W. Haley, and D. I. Draganov Dominant Role of Paraoxonases in Inactivation of the Pseudomonas aeruginosa Quorum-Sensing Signal N-(3-Oxododecanoyl)-L-Homoserine Lactone Infect. Immun., June 1, 2008; 76(6): 2512 - 2519. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D J Hausenloy and D M Yellon Targeting residual cardiovascular risk: raising high-density lipoprotein cholesterol levels Heart, June 1, 2008; 94(6): 706 - 714. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Bhattacharyya, S. J. Nicholls, E. J. Topol, R. Zhang, X. Yang, D. Schmitt, X. Fu, M. Shao, D. M. Brennan, S. G. Ellis, et al. Relationship of Paraoxonase 1 (PON1) Gene Polymorphisms and Functional Activity With Systemic Oxidative Stress and Cardiovascular Risk JAMA, March 19, 2008; 299(11): 1265 - 1276. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Senol, A. Ersoy, S. Erdinc, E. Sarandol, and M. Yurtkuran Oxidative stress and ferritin levels in haemodialysis patients Nephrol. Dial. Transplant., February 1, 2008; 23(2): 665 - 672. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Levy, K. Trudel, M. Bendayan, E. Seidman, E. Delvin, M. Elchebly, J.-C. Lavoie, L.-P. Precourt, D. Amre, and D. Sinnett Biological role, protein expression, subcellular localization, and oxidative stress response of paraoxonase 2 in the intestine of humans and rats Am J Physiol Gastrointest Liver Physiol, December 1, 2007; 293(6): G1252 - G1261. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Cronin, M. J Greenway, J. H M Prehn, and O. Hardiman Paraoxonase promoter and intronic variants modify risk of sporadic amyotrophic lateral sclerosis J. Neurol. Neurosurg. Psychiatry, September 1, 2007; 78(9): 984 - 986. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. J. Ng, N. Bourquard, S. Y. Hama, D. Shih, V. R. Grijalva, M. Navab, A. M. Fogelman, and S. T. Reddy Adenovirus-Mediated Expression of Human Paraoxonase 3 Protects Against the Progression of Atherosclerosis in Apolipoprotein E-Deficient Mice Arterioscler Thromb Vasc Biol, June 1, 2007; 27(6): 1368 - 1374. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. I. Draganov Human PON3, Effects Beyond the HDL: Clues From Human PON3 Transgenic Mice Circ. Res., April 27, 2007; 100(8): 1104 - 1105. [Full Text] [PDF]
|
|
|
|
|
|
D. M. Shih, Y.-R. Xia, X.-P. Wang, S. S. Wang, N. Bourquard, A. M. Fogelman, A. J. Lusis, and S. T. Reddy Decreased Obesity and Atherosclerosis in Human Paraoxonase 3 Transgenic Mice Circ. Res., April 27, 2007; 100(8): 1200 - 1207. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. A. Stoltz, E. A. Ozer, C. J. Ng, J. M. Yu, S. T. Reddy, A. J. Lusis, N. Bourquard, M. R. Parsek, J. Zabner, and D. M. Shih Paraoxonase-2 deficiency enhances Pseudomonas aeruginosa quorum sensing in murine tracheal epithelia Am J Physiol Lung Cell Mol Physiol, April 1, 2007; 292(4): L852 - L860. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. K. Roberts, C. Ng, S. Hama, A. J. Eliseo, and R. J. Barnard Effect of a short-term diet and exercise intervention on inflammatory/anti-inflammatory properties of HDL in overweight/obese men with cardiovascular risk factors J Appl Physiol, December 1, 2006; 101(6): 1727 - 1732. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. J. Ng, N. Bourquard, V. Grijalva, S. Hama, D. M. Shih, M. Navab, A. M. Fogelman, A. J. Lusis, S. Young, and S. T. Reddy Paraoxonase-2 Deficiency Aggravates Atherosclerosis in Mice Despite Lower Apolipoprotein-B-containing Lipoproteins: ANTI-ATHEROGENIC ROLE FOR PARAOXONASE-2 J. Biol. Chem., October 6, 2006; 281(40): 29491 - 29500. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Saeed, N. Siddique, W. Y. Hung, E. Usacheva, E. Liu, R. L. Sufit, S. L. Heller, J. L. Haines, M. Pericak-Vance, and T. Siddique Paraoxonase cluster polymorphisms are associated with sporadic ALS Neurology, September 12, 2006; 67(5): 771 - 776. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Mackness, R. Quarck, W. Verreth, M. Mackness, and P. Holvoet Human Paraoxonase-1 Overexpression Inhibits Atherosclerosis in a Mouse Model of Metabolic Syndrome Arterioscler Thromb Vasc Biol, July 1, 2006; 26(7): 1545 - 1550. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. S. Carlson, P. J. Heagerty, T. S. Hatsukami, R. J. Richter, J. Ranchalis, J. Lewis, T. J. Bacus, L. A. McKinstry, G. D. Schellenberg, M. Rieder, et al. TagSNP analyses of the PON gene cluster: effects on PON1 activity, LDL oxidative susceptibility, and vascular disease J. Lipid Res., May 1, 2006; 47(5): 1014 - 1024. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Ranade, T. G. Kirchgessner, O. A. Iakoubova, J. J. Devlin, T. DelMonte, P. Vishnupad, L. Hui, Z. Tsuchihashi, F. M. Sacks, M. S. Sabatine, et al. Evaluation of the Paraoxonases as Candidate Genes for Stroke: Gln192Arg Polymorphism in the Paraoxonase 1 Gene Is Associated With Increased Risk of Stroke Stroke, November 1, 2005; 36(11): 2346 - 2350. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. I. Draganov, J. F. Teiber, A. Speelman, Y. Osawa, R. Sunahara, and B. N. La Du Human paraoxonases (PON1, PON2, and PON3) are lactonases with overlapping and distinct substrate specificities J. Lipid Res., June 1, 2005; 46(6): 1239 - 1247. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Chait, C. Y. Han, J. F. Oram, and J. W. Heinecke Thematic review series: The Immune System and Atherogenesis. Lipoprotein-associated inflammatory proteins: markers or mediators of cardiovascular disease? J. Lipid Res., March 1, 2005; 46(3): 389 - 403. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. J. Barter, S. Nicholls, K.-A. Rye, G.M. Anantharamaiah, M. Navab, and A. M. Fogelman Antiinflammatory Properties of HDL Circ. Res., October 15, 2004; 95(8): 764 - 772. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Aharoni, L. Gaidukov, S. Yagur, L. Toker, I. Silman, and D. S. Tawfik Directed evolution of mammalian paraoxonases PON1 and PON3 for bacterial expression and catalytic specialization PNAS, January 13, 2004; 101(2): 482 - 487. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Rosenblat, T. Hayek, K. Hussein, and M. Aviram 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, January 1, 2004; 24(1): 175 - 180. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Gouedard, N. Koum-Besson, R. Barouki, and Y. Morel Opposite Regulation of the Human Paraoxonase-1 Gene PON-1 by Fenofibrate and Statins Mol. Pharmacol., April 1, 2003; 63(4): 945 - 956. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Rosenblat, D. Draganov, C. E. Watson, C. L. Bisgaier, B. N. La Du, and M. Aviram Mouse Macrophage Paraoxonase 2 Activity Is Increased Whereas Cellular Paraoxonase 3 Activity Is Decreased Under Oxidative Stress Arterioscler Thromb Vasc Biol, March 1, 2003; 23(3): 468 - 474. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Wang, Z. Fan, J. Huang, S. Su, Q. Yu, J. Zhao, R. Hui, Z. Yao, Y. Shen, B. Qiang, et al. Extensive Association Analysis Between Polymorphisms of PON Gene Cluster With Coronary Heart Disease in Chinese Han Population Arterioscler Thromb Vasc Biol, February 1, 2003; 23(2): 328 - 334. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Rantala, M.-L. Silaste, A. Tuominen, J. Kaikkonen, J. T. Salonen, G. Alfthan, A. Aro, and Y. A. Kesaniemi Dietary Modifications and Gene Polymorphisms Alter Serum Paraoxonase Activity in Healthy Women J. Nutr., October 1, 2002; 132(10): 3012 - 3017. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Satoh, P. Taylor, W. F. Bosron, S. P. Sanghani, M. Hosokawa, and B. N. L. Du Current Progress on Esterases: From Molecular Structure to Function Drug Metab. Dispos., May 1, 2002; 30(5): 488 - 493. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. S. Ng, G. F. Maguire, J. Wylie, A. Ravandi, W. Xuan, Z. Ahmed, M. Eskandarian, A. Kuksis, and P. W. Connelly Oxidative Stress Is Markedly Elevated in Lecithin:Cholesterol Acyltransferase-deficient Mice and Is Paradoxically Reversed in the Apolipoprotein E Knockout Background in Association with a Reduction in Atherosclerosis J. Biol. Chem., March 29, 2002; 277(14): 11715 - 11720. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. N. La Du Is Paraoxonase-3 Another HDL-Associated Protein Protective Against Atherosclerosis? Arterioscler Thromb Vasc Biol, April 1, 2001; 21(4): 467 - 468. [Full Text] [PDF]
|
|
|
|
|
|
C. J. Ng, D. J. Wadleigh, A. Gangopadhyay, S. Hama, V. R. Grijalva, M. Navab, A. M. Fogelman, and S. T. Reddy 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., November 21, 2001; 276(48): 44444 - 44449. [Abstract] [Full Text] [PDF]
|
|