Arterial injury by cholesterol oxidation products causes endothelial dysfunction and arterial wall cholesterol accumulation

Cholesterol oxidation products (ChOx) have been reported to cause acute vas cular injury in vivo; however, the pharmacokinetics of ChOx after administr ation and the mechanisms by which they cause chronic vascular injury are no t well understood. To further study the pharmacokinetics and atherogenic pr operties of ChOx, New Zealand White rabbits were injected intravenously (70 mg per injection, 20 injections per animal) with a ChOx mixture having a c omposition similar to that found in vivo during a 70-day period. Total ChOx concentrations in plasma peaked almost immediately after a single injectio n, 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 f raction of LDL and VLDL. Rabbit serum and the isolated LDL/VLDL fraction co ntaining elevated ChOx concentrations were cytotoxic to V79 fibroblasts and rabbit aortic endothelial cells. At the time of killing, cholesterol level s in the aortas from ChOx-injected rabbits were significantly elevated desp ite the fact that plasma cholesterol levels remained in the normal range. I n addition, aortas from the ChOx-injected rabbits retained more I-125-label ed horseradish peroxidase, measured 20 minutes after intravenous injection. Transmural concentration profiles across the arterial wall also showed inc reased horseradish peroxidase accumulation in the inner half of the media f rom the thoracic aorta in ChOx-injected rabbits. In conclusion, ChOx inject ion resulted in accumulation of circulating ChOx and induced increased vasc ular permeability and accumulation of lipids and macromolecules. This study reveals that even under normocholesterolemic conditions, ChOx can cause en dothelial dysfunction, increased macromolecular permeability, and increased cholesterol accumulation, parameters believed to be involved in the develo pment of early atherosclerotic lesions.