© 1998 American Heart Association, Inc.
Original Contributions |
Arterial Injury by Cholesterol Oxidation Products Causes Endothelial Dysfunction and Arterial Wall Cholesterol Accumulation
From the Department of Pathology (J.X.R., A.S.), Division of Cardiology (R.D., H.N.H.), and Atherosclerosis Research Unit (H.N.H., A.S.), School of Medicine, and Department of Molecular Pharmacology and Toxicology, School of Pharmacy (L.S., Y.H.C., H.P., H.N.H., A.S.), University of Southern California, Los Angeles, Calif; and Department of Cell Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio (S.R., G.M.C.).
Correspondence to Alex Sevanian, Department of Molecular Pharmacology and Toxicology, School of Pharmacy, University of Southern California, 1985 Zonal Ave, Los Angeles, CA 90033. E mail asevan@hsc.usc.edu
Abstract—Cholesterol oxidation products (ChOx) have been reported to cause acute vascular injury in vivo; however, the pharmacokinetics of ChOx after administration and the mechanisms by which they cause chronic vascular injury are not well understood. To further study the pharmacokinetics and atherogenic properties of ChOx, New Zealand White rabbits were injected intravenously (70 mg per injection, 20 injections per animal) with a ChOx mixture having a composition similar to that found in vivo during a 70-day period. Total ChOx concentrations in plasma peaked almost immediately after a single injection, declined rapidly, and returned to preinjection levels in 2 hours. After multiple injections, the ChOx concentrations rose gradually to levels 2- to 3-fold above baseline levels, increasing mostly in the cholesteryl ester fraction of LDL and VLDL. Rabbit serum and the isolated LDL/VLDL fraction containing elevated ChOx concentrations were cytotoxic to V79 fibroblasts and rabbit aortic endothelial cells. At the time of killing, cholesterol levels in the aortas from ChOx-injected rabbits were significantly elevated despite the fact that plasma cholesterol levels remained in the normal range. In addition, aortas from the ChOx-injected rabbits retained more 125I-labeled horseradish peroxidase, measured 20 minutes after intravenous injection. Transmural concentration profiles across the arterial wall also showed increased horseradish peroxidase accumulation in the inner half of the media from the thoracic aorta in ChOx-injected rabbits. In conclusion, ChOx injection resulted in accumulation of circulating ChOx and induced increased vascular permeability and accumulation of lipids and macromolecules. This study reveals that even under normocholesterolemic conditions, ChOx can cause endothelial dysfunction, increased macromolecular permeability, and increased cholesterol accumulation, parameters believed to be involved in the development of early atherosclerotic lesions.
Key Words: oxysterols • atherosclerosis • cytotoxicity • vascular injury • cholesteryl esters
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