A far-ranging program of research on lipoproteins and how they induce atherosclerosis is proposed. The goal is to establish the nature of the lipoprotein-artery wall interactions that contribute to lesion formation. At the cellular level, emphasis will be placed on the interactions between lipoproteins and macrophages and smooth muscle cells, interactions that somehow lead to the generation of foam cells, the hallmark of the earliest atherosclerotic lesion. Many fines of evidence point to oxidative modification of low density lipoprotein (LDL) as an important component of fatty streak formation but the molecular mechanisms involved remain to be fully characterized. Studies are proposed that could clarify this and, at the same time, suggest new ways in which oxidative modification might be controlled in vitro and, eventually, in vivo. Another major component of the proposed program relates to the differentiation of monocytes into tissue macrophage, attempting to define the transcriptional control of gene expression during that transition, especially of genes implicated in oxidative modification of LDL and its recognition by macrophage receptors. Animal studies are directed at understanding the reasons for differences in susceptibility to atherosclerosis of different regions in the artery wall. These studies will utilize physiological and biochemical approaches, including in situ hybridization and the PCR reaction to identify genes expressed in susceptible versus nonsusceptible sites. Even very minor modifications of LDL, including oxidative modification and glucosylation, make it antigenic and autoantibodies against these modified forms have been demonstrated in animals and in humans. Studies are proposed to further define these autoantibodies, to study their correlation with risk of coronary artery disease and to evaluate their contribution to the pathogenesis of atherosclerosis. In view of the building evidence that oxidative modification of LDL plays an important role in atherogenesis, interventions that may inhibit the process will be studied in humans and in experimental animals. Naturally occurring antioxidants and synthetic antioxidants will be studied as well as inhibitors of enzymes involved in oxidative modification. The goal of these clinical studies is to provide information on the basis of which a clinical intervention trial can eventually be planned in a rational way.
