Cholesterol oxidation products induce vascular foam cell lesion formation in hypercholesterolemic New Zealand White rabbits

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 availabl e. 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 cholest erol intake during a 78-day period, total plasma cholesterol exposures (cum ulative 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 th e aorta. Twenty injections of a ChOx mixture (70 mg per injection) were mad e bearing an oxysterol composition similar to that found in circulating oxi datively modified low density lipoprotein. At sacrifice, the ChOx-injected rabbits (n=5) had (1) significantly higher plasma ChOx levels, (2) signific antly increased cholesterol content in the aortas, mainly as esterified cho lesterol, and (3) significantly greater sudanophilic lesion size and freque ncy in the aortas compared with vehicle-injected control rabbits (n=5). The aortic cholesterol content and extent of sudanophilic lesion area were cor related significantly with total plasma ChOx exposure (P<0.003 and P<0.0001 , respectively) but not with total cholesterol exposure. The results indica te that for moderate experimental hypercholesterolemia, a situation more re levant to physiological hypercholesterolemia in humans, circulating ChOx ma y play an important role in inducing formation of early atherosclerotic les ions. Because ChOx are often present in cholesterol-containing diets, foam cell lesion formation induced by ChOx rather than cholesterol cannot be ove rlooked.