Oxidation of low-density lipoprotein and macrophage derived foam cells

Low density lipoprotein (LDL) is rich in unsaturated lipids and despite containing endogenous antioxidants is susceptible to peroxidation 111. This chemical reaction in the lipid phase of the molecule generates aldehydes which readily react with the &-amino groups of lysyl residues on the apo B protein [2]. This results in a progressive decrease in the positive charge on the molecule, a conformational change and consequent recognition by the macrophage scavenger receptor 12, 31. Uptake of oxidized LDL by the macrophage occurs through this receptor and also through some other as yet unidentified route 131. The capacity for uptake of oxidized LDL is many times greater than for native LDL and the cells can become lipid laden. The large vacuoles of lipid which form in these cells after scavenging oxidized LDL give them a 'foamy' appearance and are an early feature of atherosclerotic lesions [4]. This fact, together with the observation that oxidation of LDL occurs within areas of plaque, had led to the suggestion that it plays a key role in the pathogenesis of atherosclerosis [5]. The changes which occur during atherogenesis are complex, involving smooth muscle cell proliferation, formation of macrophage-derived foam cells and changes in the endothelium. The agents mediating these processes are largely unknown and it has been suggested that some of them may be derived from oxidized LDL or macrophage-derived foam cells [2-61. The macrophage may contribute to the development of the lesion by the production of inflammatory agents such as platelet-derived growth factor, tumour necrosis factor (TNF ) and interleukin1 (IL-I) [4, 71 but would also seem to serve an essential protective function in scavenging oxidized LDL which is known to be toxic to other cells in the artery wall [8]. It has already been demonstrated in isolated peritoneal macrophages that oxidized LDL is able to repress the expression of mRNA for TNF and IL-1 161. This result suggests that the biochemical response of the macrophage to oxidized LDL may be important in determining the role of the foam cell in the progression of the lesion. In this study we have begun to characterize the effects on the macrophage of the uptake of oxidized LDL with particular reference to the cell's ability to combat the considerable oxidative stress which must be associated with the detoxification of this molecule. In addition we have attempted to determine the mechanism by which oxidized LDL may suppress the synthesis of TNF mRNA.