Role of endothelial cell adhesion molecules and chemoattractants in atherosclerosis

Abstract

OxLDL primarily due to its lipid moiety, may potentially activate cytoprotective mechanisms, like a stress response, or lead to cell death, in the forms of necrosis or apoptosis. Incubation of cultured human endothelial cells with OxLDL triggers a stress response, with the synthesis of the inducible form of hsp70. This stress response, which is driven by the lipid moiety of OxLDL, pertains to proliferating cells, is inhibited by simvastatin and specifically involves the biosynthesis of geranylgeraniol. Incubation of endothelial cells with relatively high concentrations of OxLDL can also activate an apoptotic pathway, as demonstrated by the increase of the ratio Bax/Bcl-2 ratio, by the activation of CPP-32 and by labeling of 3~-OH termini of fragmented DNA (TUNEL} in cultured human endothelial cells. Both the above responses to OxLDL, can be elicited also by lipid-derived, water-soluble products of oxidation, an observation which broadens the potential for a role of OxLDL in affecting vessel wall functionality. The biological relevance of these in uitro data is substantiated by ex uiuo observations on early intimal thickening of human and animal aorta, where in fact OxLDL epitopes were found to associate with the inducible form of hsp70, as well as with several markers ofapoptosis. Which factor(s) besides the local concentration of OxLDL. direct toward survival or cell death is presently under investigation. Of possible relevance is also the inhibitory effect of OxLDL on endothelial secretion of MMP-9, an effect which may indirectly favour the sequestration of monocytes/macrophages into the vessel wall in the early phases of atherosclerosis.