MOLECULAR MECHANISMS CELL COMMUNICATIONS/ATHEROGENESIS

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Atherosclerosis, the underlying cause of most morbidity and mortality in the Western world, results from a focal imbalance of the normal equilibria of the artery wall. While metabolic cooperation between vascular cells is essential for the maintenance of normal artery, very little is known about the nature of cellular interactions or how they are disturbed during the recruitment of monocyte-macrophages during atherogenesis. Failure of endothelial-mediated arterial relaxation is a prominent example of communication dysfunction in hypercholesterolemia and atherosclerosis. We will examine the hypothesis that compromised gap junctional (Gj) communication in hypercholesterolemia is responsible for inhibition of vasoregulation in atherogenesis. Direct cell-cell communication occurs via Gj communicating channels through which small metabolites and ions can pass between the cytoplasmic compartments of adjacent cells. Northern blot and riboprobe hybridization analyses have demonstrated that both vascular endothelial and smooth muscle cells in tissue culture express mRNA for the Gj protein connexin 43 (cxn43). In this competing renewal, we will investigate vascular endothelial and smooth muscle cell expression of Gj proteins in situ and in vitro as a function of atherogenic processes. Lesions induced during experimental hypercholesterolemia in rabbit and baboon arteries as well as fully developed atherosclerosis in human endarterectomy tissue will be probed for Gj protein transcription and translation by in situ hybridization and immunocytochemical techniques. The spatial and temporal relationships between expression in resident endothelial and smooth muscle cells, infiltrating plasma cells, and lipid filled foam cells will be studied as a function of hypercholesterolemia. In parallel in vitro studies, the influence of altered lipid environment upon vascular cells will be evaluated in terms of RNA, protein expression and functional communication (dye transfer and electrical coupling). The effects of atherogenesis and associated changes in Gj expression and upon direct electrical coupling of vascular cells will be evaluated . A recent novel finding is that lipid-filled macrophage foam cells in human atherosclerotic lesions express mRNA for cxn43 whereas the monocytes from which they are derived do not. The proposed research will delineate the mechanisms associated with vascular cells and macrophage induction of cxn43 with particular emphasis upon the cytokine environment, the role of intracellular cholesterol accumulation, and the transcriptional, translational and signal transduction mechanisms involved. These studies will address a poorly understood mechanism of vascular cell communication at the tissue, cell and molecular level as a function of atherogenesis.