An Animal Model to Study Local Oxidation of LDL and Its Biological Effects in the Arterial Wall

From the King Gustaf V Research Institute, Karolinska Hospital (F.C., A.N., J.N., J.R.), and the Department of Cell and Molecular Biology, Karolinska Institute (J.T.), Stockholm, Sweden; the Department of Medical Laboratory Sciences and Technology, Division of Clinical Chemistry, Huddinge University Hospital, Huddinge, Sweden (U.D.); the Atherosclerosis Research Center, Division of Cardiology, Department of Medicine, Cedars-Sinai Medical Center and UCLA School of Medicine, Los Angeles (P.D., P.K.S., B.C.); and the Department of Medicine, University of California, San Diego (J.L.W., W.P.), Calif.

Correspondence to Federico Calara, King Gustaf V Research Institute, Karolinska Hospital, S-171 76 Stockholm, Sweden. E-mail rcalara{at}instmed.ks.se

Abstract—Oxidized LDL (oxLDL) is present in atherosclerotic lesions and is believed to play a key role in atherogenesis. Mainly on the basis of cell culture studies, oxLDL has been shown to produce many biological effects that influence the atherosclerotic process. To study LDL oxidation in vivo, we have established a model in which Sprague-Dawley rats are given a single injection of unmodified human LDL (4 mg/kg body weight ). Within 6 hours, an accumulation of apolipoprotein B and epitopes present on oxLDL are detected in the arterial endothelium and media. The presence of oxLDL is associated with activation of the transcription factor nuclear factor-B in the endothelium as well as endothelial expression of intercellular adhesion molecule-1. Injection of LDL enriched with the antioxidant probucol resulted in arterial accumulation of apolipoprotein B, but the expression of oxLDL-specific epitopes was reduced at 24 hours. Thus, this simple model has the potential to analyze the mechanisms behind and biological effects of LDL oxidation in vivo.

Key Words: atherosclerosis • oxLDL • nuclear factor-B • intercellular adhesion molecule-1

This article has been cited by other articles:

				C. A. Gleissner, N. Leitinger, and K. Ley Effects of Native and Modified Low-Density Lipoproteins on Monocyte Recruitment in Atherosclerosis Hypertension, August 1, 2007; 50(2): 276 - 283. [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]

				A. Schiopu, J. Bengtsson, I. Soderberg, S. Janciauskiene, S. Lindgren, M. P.S. Ares, P. K. Shah, R. Carlsson, J. Nilsson, and G. N. Fredrikson Recombinant Human Antibodies Against Aldehyde-Modified Apolipoprotein B-100 Peptide Sequences Inhibit Atherosclerosis Circulation, October 5, 2004; 110(14): 2047 - 2052. [Abstract] [Full Text] [PDF]

				C. Monaco and E. Paleolog Nuclear factor {kappa}B: a potential therapeutic target in atherosclerosis and thrombosis Cardiovasc Res, March 1, 2004; 61(4): 671 - 682. [Abstract] [Full Text] [PDF]

				F. Violi, F. Micheletta, and L. Iuliano Antioxidants and atherosclerosis Eur. Heart J. Suppl., March 1, 2002; 4(suppl_B): B17 - B21. [Abstract] [PDF]

				S. Tsimikas and J. L. Witztum Measuring Circulating Oxidized Low-Density Lipoprotein to Evaluate Coronary Risk Circulation, April 17, 2001; 103(15): 1930 - 1932. [Full Text] [PDF]

				A. Niemann-Jonsson, P. Dimayuga, S. Jovinge, F. Calara, M. P. S. Ares, G. N. Fredrikson, and J. Nilsson Accumulation of LDL in Rat Arteries Is Associated With Activation of Tumor Necrosis Factor-{alpha} Expression Arterioscler Thromb Vasc Biol, October 1, 2000; 20(10): 2205 - 2211. [Abstract] [Full Text] [PDF]

				L. Hajra, A. I. Evans, M. Chen, S. J. Hyduk, T. Collins, and M. I. Cybulsky The NF-kappa B signal transduction pathway in aortic endothelial cells is primed for activation in regions predisposed to atherosclerotic lesion formation PNAS, August 1, 2000; 97(16): 9052 - 9057. [Abstract] [Full Text] [PDF]

				L. Iuliano, A. Mauriello, E. Sbarigia, L. G. Spagnoli, and F. Violi Radiolabeled Native Low-Density Lipoprotein Injected Into Patients With Carotid Stenosis Accumulates in Macrophages of Atherosclerotic Plaque : Effect of Vitamin E Supplementation Circulation, March 21, 2000; 101(11): 1249 - 1254. [Abstract] [Full Text] [PDF]

				S. Parthasarathy, N. Santanam, S. Ramachandran, and O. Meilhac Oxidants and antioxidants in atherogenesis: an appraisal J. Lipid Res., December 1, 1999; 40(12): 2143 - 2157. [Abstract] [Full Text] [PDF]

				W. Dichtl, A. Stiko, P. Eriksson, I. Goncalves, F. Calara, C. Banfi, M. P. S. Ares, A. Hamsten, and J. Nilsson Oxidized LDL and Lysophosphatidylcholine Stimulate Plasminogen Activator Inhibitor-1 Expression in Vascular Smooth Muscle Cells Arterioscler Thromb Vasc Biol, December 1, 1999; 19(12): 3025 - 3032. [Abstract] [Full Text] [PDF]

				W. Dichtl, L. Nilsson, I. Goncalves, M. P. S. Ares, C. Banfi, F. Calara, A. Hamsten, P. Eriksson, and J. Nilsson Very Low-Density Lipoprotein Activates Nuclear Factor-{kappa}B in Endothelial Cells Circ. Res., May 14, 1999; 84(9): 1085 - 1094. [Abstract] [Full Text] [PDF]