BONE MARROW TRANSPLANTATION AND ATHEROSCLEROSIS

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Mounting evidence supports the view that atherosclerosis is a chronic inflammatory disease, process. Prostaglandins are important mediators of inflammation that are produced by endothelial cells, monocyte/macrophages, and smooth muscle cells in the artery wall. Cyclooxygensae (COX) is the rate-limiting enzyme in the production of PGs from arachidonic acid. COX exists in two isoforms, COX-1 and COX-2, that are encoded by two separate genes. COX-1 is constitutively expressed in most tissues mediating "housekeeping" functions of the cells. In contrast, COX-2 expression is normally not detectable in most tissues but its expression is rapidly induced during inflammation by a variety agents, including cytokines and growth factors. COX-2 is expressed in atherosclerotic lesions suggesting that it may play an important role in mediating inflammation in atherosclerosis. In Specific Aim 1, we will examine the hypothesis that inhibition of the inflammatory process in apoE deficient mice by selective inhibition of COX-2 will result in decreased atherosclerosis. The availability of mice with targeted disruption of the genes for COX-1 and COX-2, provides a powerful tool to investigate the contributions of these genes to atherosclerosis. In Specific Aim 2, we will examine the hypothesis that mice null for COX-2 gene expression will be protected from atherosclerosis. COX-2 is expressed by several cells in the vasculature, including endothelium, smooth muscle, and macrophages. Bone marrow transplantation studies in COX-2 deficient mice provides an approach for dissecting out the contribution of macrophage expression of COX-2 in atherosclerosis. The proposed studies should provide new insights into the physiological relevance in vivo of COX-1 and COX-2 expression in atherosclerosis. By furthering our understanding of the role of inflammation in atherosclerosis, these studies may provide the rationale for new therapeutic approaches to the prevention of atherosclerosis.