Atherosclerosis remains the major cause of morbidity and mortality in the Western world. Although lifestyle changes and hypolipidemic therapy decrease clinical events and even morality in high risk groups, there remains substantial diversity in the clinical expression of atherosclerosis for any given plasma cholesterol level. Among the many factors that go 'beyond cholesterol', much evidence supports the 'oxidation hypothesis' in the causation of atherosclerosis. This hypothesis states that the oxidative modification of LDL is a quantitatively important event in the atherogenic process. An important corollary is that measures that inhibit oxidation will decrease atherosclerosis. While the original interest in this hypothesis derived from observations that oxidation of LDL (OxLDL) is a prerequisite for macrophage uptake and foam cell formation, it is now apparent that OxLDL and its products can adversely effect the artery wall in many ways that are proinflammatory and proatherogenic. Investigators from around the world have propelled the oxidation hypothesis to the forefront of atherosclerosis research. The goal of the La Jolla SCOR program is to continue to intensively investigate the role of oxidation of LDL (and other lipoproteins) in the atherogenic process. We will investigate the molecular and cellular mechanisms involved in oxidation of LDL in vivo with particular emphasis on the role that macrophage-specific genes play. We will characterize the mechanisms responsible for macrophage-specific expression of the SR-A gene and utilize this information to achieve macrophage- specific overexpression in transgenic mice of genes that could affect the atherogenic process, such as 15-lipoxygenase. We will also develop the capacity to achieve macrophage-specific gene knockouts by use of Cre-recombinase technology. We will define the physiologic and pathophysiologic role of macrophage receptors for OxLDL with particular emphasis on CD 36 and the recently identified OxLDL-binding protein, macrosialin. We will define the importance of these receptors in vivo by generating mice that have these receptors deleted. We will determine the scope and/or limitations of antioxidant intervention in animal models of atherosclerosis and specifically test the hypothesis that for any given set of pro-oxidant stimuli, there is a threshold of antioxidant protection needed. We will investigate the role of the immune response to OxLDL with emphasis on the role of the humoral immune system and its effect on atherogenesis. We will determine the epidemiologic relationship of autoantibody titers to epitopes of OxLDL in clinical populations with respect to clinical and morphological measures of atherosclerosis and the ability of these titers to predict progression of disease. We will determine if immune complexes with LDL are found in plasma of human and animal models of atherosclerosis and if epitopes of OxLDL are found in circulating LDL. Finally, we will determine the impact of diabetes on the susceptibility of lipoproteins to oxidation. In summary, the La Jolla SCOR program proposes a multidisciplinary approach to determine the role that oxidative modification of lipoproteins could play in the atherogenic process. These insights may lead to improved and novel approaches to the prevention of atherosclerosis.
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