Abstract :
The earliest morphological change in atherosclerosis is a focal attachment of monocytes to a morphologically intact endothelium, preceeding the accumulation of monocyte-derived macrophages in the arterial intima and their subsequent transformation in lipid-laden cells (foam cells). This sequence of events leads to the appearance of the fatty streak, which precedes the development of more advanced (raised) lesions. The mechanisms by which endothelial cells, normally unreactive towards circulating monocytes, support monocyte adhesion are now beginning to be unravelled in molecular detail. In vitro stimulation of endothelial cells with bacterial endotoxin, interleukin-1, interleukin-4, or tumor-necrosis factor, elicits programmed sets of endothelial responses involving the activation of transcription of genes encoding an array of molecules controlling the different phases of leukocyte braking (“rolling”) in the proximity of endothelial surface, arrest, spreading and diapedesis. Pivotal in this process is the synthesis of endothelial-leukocyte adhesion molecules - able to tether and to stably attach leukocytes onto vascular endothelium - and of leukocyte-specific chemoattractants - able to elicit leukocyte movement towards a chemotaxis gradient. The origin of atherosclerosis can thus be viewed as a site- and cell-specific type of inflammatory reaction. The type of endothelium involved (e.g. arterial endothelium at particular sites), the nature of the stimulus involved (e.g., oxidized low-density lipoproteins, advanced glycosylation end-products), of secondary mediators elicited (e.g., specific cytokines), and the set of adhesion molecules and chemoattractants produced by endothelial cells, may explain the localization and the type of local reaction thus initiated. Endothelial activation, i.e. the process by which endothelial cells, normally unreactive towards circulating leukocytes, acquire - among other new properties - the ability to support leukocyte attachment, appears to be a novel site of mechanistic action for risk factors of atherosclerosis and for nutritional and pharmacological strategies in preventing this disease. Similar stragegies may now be devised in the control of acute inflammation, the basic mechanisms of which, tissue infiltration with neutrophils, is based on similar mechanistic steps (leukocyte chemoattraction, endothelial binding and diapedesis) as in atherogenesis. In our presentation we will review the evidence we recently gathered on the modulability of gene transcription, cell surface adhesion molecule expression and physiological consequences of this in terms of leukocyte adhesion, by either exogenous modulators (dietary fatty acids) or endogenous mediators (nitric oxide). An important role for the nuclear factor-κB (NF-κB) set of transcription factors is now demonstrated in the case of nitric oxide and believed probable in the case of fatty acids.
