There is now considerable evidence, both in animals and in humans, that oxidative modification of LDL is ongoing in vivo and that it plays an important role in the atherogenic process. Ultimately, the crucial test of this hypothesis in man will come from controlled clinical studies in which therapies known to protect LDL from oxidation are tested as to their efficacy in inhibiting the atherogenic process and its clinical manifestations. The primary goal of this unit is to develop and evaluate effective and practical therapeutic modalities that will protect LDL from oxidation so that a clinical trial can be rationally designed to test the role of oxidation of LDL in the atherogenic process. In addition we will test the hypothesis that in patients whose LDL are more susceptible to oxidation and/or in whom monocytes have an increased potential to oxidize LDL may be at high risk for atherosclerosis and its complications. We will also test the hypothesis that markers for the presence of early changes indicative of LDL oxidation can be detected in the plasma of such high risk subjects and that the presence of autoantibodies to epitopes of oxidized LDL are one such marker system. Specifically, we will test whether dietary supplementation with one or more natural antioxidants, such as beta-carotene, vitamin E, or vitamin C, given alone or in combination, will lead to increased protection of LDL against oxidative modification. Because unsaturated fatty acids in the LDL are the initial substrate for oxidative attack, we will test the hypothesis that replacement of unsaturated fatty acids with monounsaturated, or selected saturated fatty acids, will be another strategy that will effectively inhibit LDL susceptibility to modification. We will also continue our studies with the potent lipophilic antioxidant drug, probucol, to determine its optimal use with respect to protection of LDL, as well as to test the possibility that enrichment of the cellular content with probucol may inhibit the ability of cells to modify LDL. In addition, we will compare the susceptibility to oxidation of LDL isolated from patients with known CAD, or at increased risk for CAD, and determine if there are differences from a normal population. We will also study selected kindreds with increased risk for CAD to determine if steps in the oxidative modification pathway, might be uniquely enhanced.
