Cellular mechanisms of human atherosclerosis: Role of cell-to-cell communications in subendothelial cell functions

Abstract

The present study was undertaken in order to extend of our earlier work, focusing on the analysis of roles of cell-to-cell communications in the regulation of the subendothelial cell function. In present study, we have found that the expression of connexin43 (Cx43) is dramatically reduced in human atherosclerotic lesions, compared with undiseased intima. In atherosclerotic lesions, the number of so-called 'connexin plaques' was found to be lower in lipid-laden cells than in cells which were free from lipid inclusions. In primary cell culture, subendothelial intimal cells tended to create multicellular structures in the form of clusters. Cluster creation was accompanied by the formation of gap junctions between cells; the degree of gap junctional communication correlated with the density of cells in culture. We found that atherosclerosis-related processes such as DNA synthesis, protein synthesis and accumulation of intracellular cholesterol correlated with the degree of cell-to-cell communication. The relation of DNA and protein synthesis with cell-to-cell communication could be described as "bell-shaped". We further incubated cells, cultured from undiseased subendothelial intima, with various forms of modified LDL causing intracellular cholesterol accumulation. After the incubation of intimal cells with modified LDL, intercellular communication has "dropped" considerably. The findings indicate that intracellular lipid accumulation might be a reason for a decrease of the number of gap junctions. The findings also suggest that the disintegration of cellular network is associated with foam cell formation, the process known as a key event of atherogenesis.