This Program Project application has as its central theme, the definition of the elements of lipoprotein metabolism related to coronary artery atherosclerosis. The preceding three decades have seen tremendous strides forward in our understanding of hyperlipoproteinemia and its relationship to coronary heart disease (CHD). However, many questions remain. In this Program Project, we are proposing to study the manner by which dietary fatty acids promote or protect against coronary artery atherosclerosis. We have developed data suggesting that certain dietary fatty acids promote or protect against coronary artery atherosclerosis. We will monitor the relative importance of LDL cholesterol concentration versus LDL composition as modified by dietary fatty acids by establish groups of African green monkeys with equivalent LDL cholesterol concentrations. In this case, the primary variable in atherosclerosis outcome is LDL composition, although the HDL cholesterol concentrations will also be measured and considered. We are proposing to examine the interactions of LDL with smooth muscle cells as they affect the production of arterial proteoglycans as a potential mechanism of atherogenesis. We have derived data showing diet-specific effects, i.e. LDL from mono unsaturated fat fed versus n-3 polyunsaturated fat-fed monkeys caused decreasing PG synthesis. In addition, we will investigate dietary fatty acid effects on a transgenic mouse model with markedly elevated plasma LDL cholesterol concentrations as a potential model in which to examine genetic aspects of diet-atherosclerosis-lipoprotein interactions. We will study the metabolic pathways through which plasma HDL levels are modified by dietary fat, and will evaluate the importance of dietary fat-induced modifications in HDL subpopulations in the atherosclerosis outcome. We will examine the pathways through which apoB-containing lipoproteins are assembled and secreted and how this process is regulated. We will examine the specific characteristics of apoA-I that contribute to HDL particle formation and stability. Finally, we will examine relationships between bile acids and the development of hyperlipoproteinemia, and define the physiologic and pathophysiologic implications. All of these efforts support the theme of the Program-to identify specific aspects in the regulation of lipoprotein metabolism as it affects coronary artery atherosclerosis. All of the programs are interrelated and yet contribute distinct types of basic information. Progress in these research areas will provide opportunities in the future for treatment of Coronary Heart Disease.
Showing the most recent 10 out of 242 publications
