Effects of differently oxidized LDL on the expression of pro-inflammatory molecules in human monocytes in vitro

The oxidation of low-density lipoprotein (LDL) is thought to be a major contributor to the development of atherosclerosis and considerable evidence has accumulated showing that oxidized LDL (ox LDL) induces cell damage and pro-atherogenic events. However, evidence that oxidized LDL directly causes atherosclerosis is lacking. We studied whether native and enzymatically or chemically ox LDL at concentrations of 5 and 100 microg/mL is cytotoxic to or promotes pro-atherogenic activation of human primary monocytes in culture. Both types of ox LDL (100 microg/mL), but not native LDL added to monocytes for 24 h significantly diminish DNA synthesis and increase cell death. In addition, both preparations of ox LDL inhibit cytokine and metalloproteinase production, diminish cellular oxygen consumption and induce PPAR gamma expression. Enzymatically ox LDL, but not LDL oxidized by copper sulfate, also increases the monocyte metabolic rate and induces intracellular lipid accumulation. Low concentrations of either preparation of oxidized and native LDL did not show significant effects on all parameters measured. These data establish a direct link between ox LDL concentration and cytotoxicity and suggest that oxidation by copper of the lipid moiety in LDL and of the protein moiety by enzyme creates ox LDL, which can damage monocytes without release of pro-inflammatory molecular species. In contrast to native and enzymatically ox LDL, copper ox LDL does not induce intracellular lipid accumulation. Differently oxidized LDL molecules may exert distinct effects in lesion development in atherosclerosis.