Atherosclerosis and its complications are a major cause of morbidity and mortality in industrialized nations. Although risk factors for atherosclerosis have been identified, the cellular and molecular mechanisms of atherosclerotic lesion initiation are not fully understood. There is increasing evidence that vascular endothelium may play a key role in the pathogenesis of atherosclerosis. This application proposes to study the role of endothelium in regulating one of the earliest events observed in atherogenesis: the adherence of blood monocytes to the arterial luminal surface, a necessary step in their accumulation in the intima and transformation into foam cells. The recent identification by the applicant of a leukocyte adhesion molecule in the rabbit (designated ATHERO-ELAM), which appears to be monocyte-directed, and is expressed selectively by arterial endothelial cells covering early foam cell lesions will allow molecular characterization of monocyte-endothelial interactions during atherogenesis. The primary goals of the proposed research are to (a) characterize the leukocyte adhesive function of ATHERO-ELAM, (b) elucidate its primary structure, (c) determine whether relevant pathophysiologic stimuli including cytokines and native, or altered, serum lipoproteins can upregulate its expression, and (d) identify other endothelial adhesion molecules with similar properties. The characterization of the function of ATHERO-ELAM will utilize monoclonal antibodies to block rabbit monocyte adhesion to cultured endothelial cells and aortic explants. The role of ATHERO-ELAM in the initiation of atherosclerotic lesions will be examined by blocking monocyte adhesion to the arterial lining of genetically hypercholesterolemic rabbits in vivo, and by comparing the temporal and topographic patterns of ATHERO-ELAM expression (determined by immunohistochemical methods) with monocyte adhesion and intimal foam cell accumulation. Finally, molecular cloning of ATHERO-ELAM will reveal its primary structure, define its relationship to known vascular adhesion molecules, and permit future studies examining the relationship of risk factors for atherosclerosis with the regulation of its expression.
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