It is now widely recognized that atherosclerosis is an inflammatory process that proceeds through several stages of development that share common features with other forms of chronic inflammatory disease. The consequence of this inflammatory reaction is fibro-proliferative plaque formation that narrows the lumenal opening of large and medium size arteries. Many studies using genetically altered mice have confirmed that the macrophage plays a critical role in mediating the chronic inflammation characteristically seen in atherosclerotic plaques. The prevailing paradigm for atherosclerosis also implicates lipid accumulation in the artery wall, particularly in macrophages, as being critical to the initiation and development of these inflammatory events. In this grant proposal, we will generated transgenic animals whose macrophages can be ablated at various time points in the development of atherosclerotic lesions through the use of drugs that activate toxins encoding by the transgenes. These experiments are intended to explore the role of proliferating macrophages in lesion development and progression and to clarify the necessity for the continue presence of macrophages for the process of atherogenesis. The grant will also make use of homologous recombinant mice that do not express the three currently established scavenger receptor family members (SR-A (type I and type II macrophage scavenger receptors), CD36, and CD68) to determine the impact of reduced modified lipoprotein uptake on lesion development. Previous work has suggested that reduced modified lipoprotein uptake does result in smaller atherosclerotic plaques in the hyperlipidemic mouse models of the disease, but no single scavenger receptor can account for more than half of the lipid ingested. By generating animals deficient in all three scavenger receptor family members, it is anticipated that this work will be able to determine the significance of foam cell formation and lipid activation of macrophages via these receptor pathways on lesion development. These studies should provide valuable insights into the role of macrophage receptors in atherogenesis that could serve as the basis for new therapeutic strategies to treat coronary heart disease and its complications.
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