Abstract
Low density lipoprotein (LDL) has been reported to be injurious or toxic to cells in vitro. This injurious effect is, in some instances, due to oxidation of the lipid moiety of the lipoprotein. The objectives of this study were to determine if the oxidation rendering the lipoprotein toxic to human skin fibroblasts occurred by free radical mechanisms, and if so, which of the common free radical oxygen species were involved. The selective free radical blockers or scavengers employed included superoxide dismutase for superoxide, catalase for hydrogen peroxide, dimethylfuran for singlet molecular oxygen, and mannitol for hydroxyl radical. The presence during lipoprotein preparation of general free radical scavengers (vitamin E, butylated hydroxytoluene) or the divalent cation chelator ethylenediamine tetraacetic acid prevented the formation of cytotoxic low density lipoprotein, while the simultaneous presence of superoxide dismutase and catalase partially inhibited its formation. The results indicate that superoxide and/or hydrogen peroxide are involved in the formation of the toxic LDL lipid. The toxic action of oxidized LDL could not be prevented by inclusion of antioxidants in the culture medium, indicating that an oxidized lipid was responsible for cell injury rather than free radicals generated in culture by the action of oxidized LDL. Three separate assays for cell injury (enumeration of attached cells, cell loss of lactate dehydrogenase into the culture medium, and trypan blue uptake) indicated a sequence of events in which the fibroblasts are injured, die, and then detach.
Highlights
Low density lipoprotein (LDL) has been reported to be injurious or toxic to cells in vitro
The presence of the antioxidant glutathione or the metal ion chelator ethylenediamine tetraacetic acid (EDTA) throughout the LDL isolation from normal plasma or serum can prevent the formation of cytotoxic LDL [79]
In the present studies we show that the oxidation of LDL which renders it cytotoxic occurs by free radical mechanisms involving superoxide and/or hydrogen peroxide
Summary
Low density lipoprotein (LDL) has been reported to be injurious or toxic to cells in vitro. T h e presence during lipoprotein preparation of general free radical scavengers (vitamin E, butylated hydroxytoluene) or the divalent cation chelator ethylenediamine tetraacetic acid prevented the formation of cytotoxic low density lipoprotein, while the simultaneous presence of superoxide dismutase and catalase partially inhibited its formati0n.l The results indicate that superoxide and/or hydrogen peroxide are involved in the formation of the toxic LDL lipid. The presence of the antioxidant glutathione or the metal ion chelator ethylenediamine tetraacetic acid (EDTA) throughout the LDL isolation from normal plasma or serum can prevent the formation of cytotoxic LDL [79] Both the TBARS and the cytotoxic agent(s) are associated with the lipid-extractable portion of the LDL molecule [8]
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