© 2001 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Circulating Autoantibodies to Oxidized LDL Correlate With Arterial Accumulation and Depletion of Oxidized LDL in LDL Receptor–Deficient Mice
From the Divisions of Cardiovascular Diseases (S.T.) and Endocrinology and Metabolism (W.P., J.L.W.), Department of Medicine, University of California, San Diego.
Correspondence to Sotirios Tsimikas, MD, Department of Medicine, Division of Cardiology, University of California San Diego, 9500 Gilman Dr, BSB 1080, La Jolla, CA 92093-0682. E-mail stsimikas{at}ucsd.edu
Abstract—Autoantibodies to oxidized low density lipoprotein (OxLDL) are elevated in some human populations with increased risk of atherosclerosis. To determine whether autoantibody levels to epitopes of OxLDL reflect the extent of aortic atherosclerosis and the content of OxLDL, we measured IgG and IgM autoantibody titers to malondialdehyde (MDA)-LDL and copper-oxidized LDL (Cu-OxLDL) in 43 LDL receptor–deficient mice consuming atherogenic and regression diets. Antibody titers were correlated to percent atherosclerotic surface area, aortic weight, and aortic OxLDL content, measured as the in vivo uptake of 125I-MDA2, a monoclonal antibody to MDA-LDL. All mice were fed an atherogenic diet for 6 months, and 1 group was euthanized. The other 3 groups were fed an atherogenic diet (fat/CHOL group), normal mouse chow (chow group), or mouse chow supplemented with vitamins E and C (chow+VIT group) for an additional 6 months. After dietary intervention, compared with their own baseline, autoantibody titers to MDA-LDL and Cu-OxLDL increased significantly in the fat/CHOL group, whereas they did not change or decreased significantly in the chow and chow+VIT groups. Aortic weight and surface area showed significant progression in the fat/CHOL group, mild progression in the chow group, and no progression in the chow+VIT group (P<0.001), whereas OxLDL content actually decreased in the latter 2 groups (P<0.001). Significant correlations were seen with MDA-LDL autoantibody titers and OxLDL content (IgM, R=0.64 and P=0.0009; IgG, R=0.52 and P=0.009), as well as with percent surface area and aortic weight. These data support the hypothesis that autoantibody titers to OxLDL reflect changes in OxLDL content in atherosclerotic lesions of LDL receptor–deficient mice. Whether autoantibody titers to OxLDL will provide similar valuable insights into the extent of human atherosclerosis, particularly anatomic measurements of plaque burden and OxLDL content, remains to be determined.
Key Words: regression • progression • atherosclerosis • lipoproteins • autoantibodies
This article has been cited by other articles:
 |
|
 |
|
  P. Sjogren, G. N. Fredrikson, A. Samnegard, C.-G. Ericsson, J. Ohrvik, R. M. Fisher, J. Nilsson, and A. Hamsten High plasma concentrations of autoantibodies against native peptide 210 of apoB-100 are related to less coronary atherosclerosis and lower risk of myocardial infarction Eur. Heart J., September 2, 2008; 29(18): 2218 - 2226. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Merki, M. J. Graham, A. E. Mullick, E. R. Miller, R. M. Crooke, R. E. Pitas, J. L. Witztum, and S. Tsimikas Antisense Oligonucleotide Directed to Human Apolipoprotein B-100 Reduces Lipoprotein(a) Levels and Oxidized Phospholipids on Human Apolipoprotein B-100 Particles in Lipoprotein(a) Transgenic Mice Circulation, August 12, 2008; 118(7): 743 - 753. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. F. Langer, R. Haubner, B. J. Pichler, and M. Gawaz Radionuclide imaging a molecular key to the atherosclerotic plaque. J. Am. Coll. Cardiol., July 1, 2008; 52(1): 1 - 12. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. C. Briley-Saebo, P. X. Shaw, W. J.M. Mulder, S.-H. Choi, E. Vucic, J. G. S. Aguinaldo, J. L. Witztum, V. Fuster, S. Tsimikas, and Z. A. Fayad Targeted Molecular Probes for Imaging Atherosclerotic Lesions With Magnetic Resonance Using Antibodies That Recognize Oxidation-Specific Epitopes Circulation, June 24, 2008; 117(25): 3206 - 3215. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Ky, A. Burke, S. Tsimikas, M. L. Wolfe, M. G. Tadesse, P. O. Szapary, J. L. Witztum, G. A. FitzGerald, and D. J. Rader The Influence of Pravastatin and Atorvastatin on Markers of Oxidative Stress in Hypercholesterolemic Humans J. Am. Coll. Cardiol., April 29, 2008; 51(17): 1653 - 1662. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Torzewski, V. Ochsenhirt, A. L. Kleschyov, M. Oelze, A. Daiber, H. Li, H. Rossmann, S. Tsimikas, K. Reifenberg, F. Cheng, et al. Deficiency of Glutathione Peroxidase-1 Accelerates the Progression of Atherosclerosis in Apolipoprotein E-Deficient Mice Arterioscler Thromb Vasc Biol, April 1, 2007; 27(4): 850 - 857. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Tsimikas, E. S. Brilakis, R. J. Lennon, E. R. Miller, J. L. Witztum, J. P. McConnell, K. S. Kornman, and P. B. Berger Relationship of IgG and IgM autoantibodies to oxidized low density lipoprotein with coronary artery disease and cardiovascular events J. Lipid Res., February 1, 2007; 48(2): 425 - 433. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. K. Bhatia, S. Yun, V. Leung, D. C. Grimsditch, G. M. Benson, M. B. Botto, J. J. Boyle, and D. O. Haskard Complement C1q Reduces Early Atherosclerosis in Low-Density Lipoprotein Receptor-Deficient Mice Am. J. Pathol., January 1, 2007; 170(1): 416 - 426. [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]
|
|
|
|
|
|
M. Mayr, S. Kiechl, S. Tsimikas, E. Miller, J. Sheldon, J. Willeit, J. L. Witztum, and Q. Xu Oxidized Low-Density Lipoprotein Autoantibodies, Chronic Infections, and Carotid Atherosclerosis in a Population-Based Study J. Am. Coll. Cardiol., June 20, 2006; 47(12): 2436 - 2443. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Tsimikas, J. T. Willerson, and P. M. Ridker C-reactive protein and other emerging blood biomarkers to optimize risk stratification of vulnerable patients. J. Am. Coll. Cardiol., April 18, 2006; 47(8 Suppl): C19 - C31. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Arakawa, J.-Y. Qian, D. Baatar, K. Karasawa, Y. Asada, Y. Sasaguri, E. R. Miller, J. L. Witztum, and H. Ueno Local Expression of Platelet-Activating Factor-Acetylhydrolase Reduces Accumulation of Oxidized Lipoproteins and Inhibits Inflammation, Shear Stress-Induced Thrombosis, and Neointima Formation in Balloon-Injured Carotid Arteries in Nonhyperlipidemic Rabbits Circulation, June 21, 2005; 111(24): 3302 - 3309. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Nilsson, G. K. Hansson, and P. K. Shah Immunomodulation of Atherosclerosis: Implications for Vaccine Development Arterioscler Thromb Vasc Biol, January 1, 2005; 25(1): 18 - 28. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Schneider, B. Verges, A. Klein, E. R. Miller, V. Deckert, C. Desrumaux, D. Masson, P. Gambert, J.-M. Brun, J. Fruchart-Najib, et al. Alterations in Plasma Vitamin E Distribution in Type 2 Diabetic Patients With Elevated Plasma Phospholipid Transfer Protein Activity Diabetes, October 1, 2004; 53(10): 2633 - 2639. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. P. Choudhury, J. X. Rong, E. Trogan, V. I. Elmalem, H. M. Dansky, J. L. Breslow, J. L. Witztum, J. T. Fallon, and E. A. Fisher High-Density Lipoproteins Retard the Progression of Atherosclerosis and Favorably Remodel Lesions Without Suppressing Indices of Inflammation or Oxidation Arterioscler Thromb Vasc Biol, October 1, 2004; 24(10): 1904 - 1909. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Traverso, S. Menini, E. P. Maineri, S. Patriarca, P. Odetti, D. Cottalasso, U. M. Marinari, and M. A. Pronzato Malondialdehyde, a Lipoperoxidation-Derived Aldehyde, Can Bring About Secondary Oxidative Damage To Proteins J. Gerontol. A Biol. Sci. Med. Sci., September 1, 2004; 59(9): B890 - B895. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Tsimikas, H. K. Lau, K.-R. Han, B. Shortal, E. R. Miller, A. Segev, L. K. Curtiss, J. L. Witztum, and B. H. Strauss Percutaneous Coronary Intervention Results in Acute Increases in Oxidized Phospholipids and Lipoprotein(a): Short-Term and Long-Term Immunologic Responses to Oxidized Low-Density Lipoprotein Circulation, June 29, 2004; 109(25): 3164 - 3170. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. P. Faxon, V. Fuster, P. Libby, J. A. Beckman, W. R. Hiatt, R. W. Thompson, J. N. Topper, B. H. Annex, J. H. Rundback, R. P. Fabunmi, et al. Atherosclerotic Vascular Disease Conference: Writing Group III: Pathophysiology Circulation, June 1, 2004; 109(21): 2617 - 2625. [Full Text] [PDF]
|
|
|
|
|
|
M. M. Engler, M. B. Engler, M. J. Malloy, E. Y. Chiu, M. C. Schloetter, S. M. Paul, M. Stuehlinger, K. Y. Lin, J. P. Cooke, J. D. Morrow, et al. Antioxidant Vitamins C and E Improve Endothelial Function in Children With Hyperlipidemia: Endothelial Assessment of Risk from Lipids in Youth (EARLY) Trial Circulation, September 2, 2003; 108(9): 1059 - 1063. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. P. Yang, D. Yan, C. Qiao, R. J. Liu, J.-G. Chen, J. Li, M. Schneider, L. Lagrost, X. Xiao, and X.-C. Jiang Increased Atherosclerotic Lesions in ApoE Mice With Plasma Phospholipid Transfer Protein Overexpression Arterioscler Thromb Vasc Biol, September 1, 2003; 23(9): 1601 - 1607. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Mertens, P. Verhamme, J. K. Bielicki, M. C. Phillips, R. Quarck, W. Verreth, D. Stengel, E. Ninio, M. Navab, B. Mackness, et al. Increased Low-Density Lipoprotein Oxidation and Impaired High-Density Lipoprotein Antioxidant Defense Are Associated With Increased Macrophage Homing and Atherosclerosis in Dyslipidemic Obese Mice: LCAT Gene Transfer Decreases Atherosclerosis Circulation, April 1, 2003; 107(12): 1640 - 1646. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Tsimikas, C. Bergmark, R. W. Beyer, R. Patel, J. Pattison, E. Miller, J. Juliano, and J. L. Witztum Temporal increases in plasma markers of oxidized low-density lipoprotein strongly reflect the presence of acute coronary syndromes J. Am. Coll. Cardiol., February 5, 2003; 41(3): 360 - 370. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. M. Cazita, J. A. Berti, C. Aoki, M. Gidlund, L. M. Harada, V. S. Nunes, E. C. R. Quintao, and H. C. F. Oliveira Cholesteryl ester transfer protein expression attenuates atherosclerosis in ovariectomized mice J. Lipid Res., January 1, 2003; 44(1): 33 - 40. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. C. Fang, S. Kinlay, D. Behrendt, H. Hikita, J. L. Witztum, A. P. Selwyn, and P. Ganz Circulating Autoantibodies to Oxidized LDL Correlate With Impaired Coronary Endothelial Function After Cardiac Transplantation Arterioscler Thromb Vasc Biol, December 1, 2002; 22(12): 2044 - 2048. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. S. Major, S. Fazio, and M. F. Linton B-Lymphocyte Deficiency Increases Atherosclerosis in LDL Receptor-Null Mice Arterioscler Thromb Vasc Biol, November 1, 2002; 22(11): 1892 - 1898. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X.-C. Jiang, A. R. Tall, S. Qin, M. Lin, M. Schneider, F. Lalanne, V. Deckert, C. Desrumaux, A. Athias, J. L. Witztum, et al. Phospholipid Transfer Protein Deficiency Protects Circulating Lipoproteins from Oxidation Due to the Enhanced Accumulation of Vitamin E J. Biol. Chem., August 23, 2002; 277(35): 31850 - 31856. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Steinberg and J. L. Witztum Is the Oxidative Modification Hypothesis Relevant to Human Atherosclerosis?: Do the Antioxidant Trials Conducted to Date Refute the Hypothesis? Circulation, April 30, 2002; 105(17): 2107 - 2111. [Full Text] [PDF]
|
|
|
|
|
|
K. Tanaga, H. Bujo, M. Inoue, K. Mikami, K. Kotani, K. Takahashi, T. Kanno, and Y. Saito Increased Circulating Malondialdehyde-Modified LDL Levels in Patients With Coronary Artery Diseases and Their Association With Peak Sizes of LDL Particles Arterioscler Thromb Vasc Biol, April 1, 2002; 22(4): 662 - 666. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Tanaga, H. Bujo, M. Inoue, K. Mikami, K. Kotani, K. Takahashi, T. Kanno, and Y. Saito Increased Circulating Malondialdehyde-Modified LDL Levels in Patients With Coronary Artery Diseases and Their Association With Peak Sizes of LDL Particles Arterioscler Thromb Vasc Biol, April 1, 2002; 22(4): 662 - 666. [Abstract] [Full Text] [PDF]
|
|