The role of cholesterol oxidation products in the pathogenesis of atherosclerosis.
Cholesterol undergoes spontaneous autoxidation, leading to the production of potentially atherogenic oxidation derivatives. When 25-hydroxycholesterol (25-OH) or cholestane-3 beta, 5 alpha, 6 beta-triol (triol) was injected intravenously into rabbits, the aortic surfaces showed numerous balloon-like protrusions and crater-like defects indicative of endothelial damage. Alterations in membrane function caused by these cholesterol oxides could be the mechanism for their cytotoxic effect. Carrier-mediated hexose transport by cultured rabbit aortic smooth muscle cells, measured using 2-deoxyglucose, was reversibly inhibited by triol within one hour. A membrane-bound enzyme, 5'-nucleotidase, was inhibited after 24 to 48 hrs incubation with either 25-OH or triol. Endocytosis was also significantly inhibited by both 25-OH and triol. Depletion of membrane cholesterol content by the cholesterol oxides could account for the membrane functional alterations. Cholesterol biosynthesis is markedly inhibited by 25-OH. Triol has a lesser effect on cholesterol biosynthesis, but it is more potent in blocking uptake of cholesterol by arterial cells in culture. Cholesterol oxides may also influence cholesteryl ester accumulation by arterial smooth muscle cells. Incubation of cells with 25-OH resulted in a four-fold increase in cholesterol esterifying activity but no effect on cholesteryl ester hydrolytic activity. The cholesterol oxides appear to be transported in the blood primarily by very low density lipoproteins (VLDL) and low density lipoproteins (LDL). Oxidized LDL has cytotoxic effects and enhances macrophage lipid accumulation. These be effects may be directly related to the cholesterol oxide content of these lipoproteins.
Morin
R J
RJ
Harbor-UCLA Department of Pathology, Medical Center, Torrance 90509.
Peng
S K
SK
D000818:Animals; D001158:Arteries / Q000378:metabolism / Q000473:pathology; D001161:Arteriosclerosis / Q000378:metabolism*; D001692:Biological Transport; D002784:Cholesterol / Q000096:biosynthesis / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D010084:Oxidation-Reduction; D013347:Subcellular Fractions / Q000378:metabolism
D002784:Cholesterol; D005947:Glucose