This Article Full Text Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rong, J. X. Articles by Sevanian, A. Search for Related Content PubMed PubMed Citation Articles by Rong, J. X. Articles by Sevanian, A. Related Collections Animal models of human disease Lipid and lipoprotein metabolism Oxidant stress

(Arteriosclerosis, Thrombosis, and Vascular Biology. 1999;19:2179-2188.)
© 1999 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Cholesterol Oxidation Products Induce Vascular Foam Cell Lesion Formation in Hypercholesterolemic New Zealand White Rabbits

James X. Rong; Lijiang Shen; Yi H. Chang; Arnis Richters; Howard N. Hodis; Alex Sevanian

From the Department of Pathology, School of Medicine (J.X.R., A.R., A.S.); the Department of Molecular Pharmacology and Toxicology, School of Pharmacy (L.S., Y.H.C., H.N.H., A.S.); the Division of Cardiology, School of Medicine (H.N.H.); and the Atherosclerosis Research Unit, School of Medicine (H.N.H., A.S.), University of Southern California, Los Angeles, Calif.

Correspondence to Alex Sevanian, Department of Molecular Pharmacology and Toxicology, USC School of Pharmacy, 1985 Zonal Ave, Los Angeles, CA 90033. E-mail asevan{at}hsc.usc.edu

Abstract—Circulating cholesterol oxidation products (ChOx) have long been implicated in the etiology of early atherosclerosis; however, direct in vivo evidence elucidating their role in atherogenesis is only recently becoming available. This study investigated ChOx effects on vascular lesion formation in New Zealand White rabbits under controlled hypercholesterolemic conditions. By closely monitoring plasma cholesterol levels and adjusting dietary cholesterol intake during a 78-day period, total plasma cholesterol exposures (cumulative plasma cholesterol levels over time) were controlled between 27 000 and 34 000 mg/dLxday (final plasma cholesterol concentration, 467±77 mg/mL), representing a threshold range for sudanophilic lesion formation in the aorta. Twenty injections of a ChOx mixture (70 mg per injection) were made bearing an oxysterol composition similar to that found in circulating oxidatively modified low density lipoprotein. At sacrifice, the ChOx-injected rabbits (n=5) had (1) significantly higher plasma ChOx levels, (2) significantly increased cholesterol content in the aortas, mainly as esterified cholesterol, and (3) significantly greater sudanophilic lesion size and frequency in the aortas compared with vehicle-injected control rabbits (n=5). The aortic cholesterol content and extent of sudanophilic lesion area were correlated significantly with total plasma ChOx exposure (P<0.003 and P<0.0001, respectively) but not with total cholesterol exposure. The results indicate that for moderate experimental hypercholesterolemia, a situation more relevant to physiological hypercholesterolemia in humans, circulating ChOx may play an important role in inducing formation of early atherosclerotic lesions. Because ChOx are often present in cholesterol-containing diets, foam cell lesion formation induced by ChOx rather than cholesterol cannot be overlooked.

Key Words: oxysterols • cholesterol feeding • foam cell lesions • hypercholesterolemia

This article has been cited by other articles:

				Y. Jiang, J. Jiang, J. Xiong, J. Cao, N. Li, G. Li, and S. Wang Homocysteine-induced extracellular superoxide dismutase and its epigenetic mechanisms in monocytes J. Exp. Biol., March 15, 2008; 211(6): 911 - 920. [Abstract] [Full Text] [PDF]

				X.-j. Zhang, D. L. Chinkes, A. Aarsland, D. N. Herndon, and R. R. Wolfe Lipid Metabolism in Diet-Induced Obese Rabbits Is Similar to That of Obese Humans J. Nutr., March 1, 2008; 138(3): 515 - 518. [Abstract] [Full Text] [PDF]

				E. Pedruzzi, C. Guichard, V. Ollivier, F. Driss, M. Fay, C. Prunet, J.-C. Marie, C. Pouzet, M. Samadi, C. Elbim, et al. NAD(P)H Oxidase Nox-4 Mediates 7-Ketocholesterol-Induced Endoplasmic Reticulum Stress and Apoptosis in Human Aortic Smooth Muscle Cells Mol. Cell. Biol., December 15, 2004; 24(24): 10703 - 10717. [Abstract] [Full Text] [PDF]

				J. M. Hayden, L. Brachova, K. Higgins, L. Obermiller, A. Sevanian, S. Khandrika, and P. D. Reaven Induction of monocyte differentiation and foam cell formation in vitro by 7-ketocholesterol J. Lipid Res., January 1, 2002; 43(1): 26 - 35. [Abstract] [Full Text] [PDF]

				K. Y. Stokes, E. C. Clanton, J. M. Russell, C. R. Ross, and D. N. Granger NAD(P)H Oxidase-Derived Superoxide Mediates Hypercholesterolemia-Induced Leukocyte-Endothelial Cell Adhesion Circ. Res., March 16, 2001; 88(5): 499 - 505. [Abstract] [Full Text] [PDF]

				C. Xu, C. K. Zarins, P. S. Pannaraj, H. S. Bassiouny, and S. Glagov Hypercholesterolemia Superimposed by Experimental Hypertension Induces Differential Distribution of Collagen and Elastin Arterioscler Thromb Vasc Biol, December 1, 2000; 20(12): 2566 - 2572. [Abstract] [Full Text] [PDF]

				H. N. Hodis, S. Hashimoto, W. J. Mack, and A. Sevanian Probucol Reduces Oxysterol Formation in Hypertensive Rabbits Hypertension, September 1, 2000; 36(3): 436 - 441. [Abstract] [Full Text] [PDF]