7-BETA-HYDROPEROXYCHOLEST-5-EN-3-BETA-OL, A COMPONENT OF HUMAN ATHEROSCLEROTIC LESIONS, IS THE PRIMARY CYTOTOXIN OF OXIDIZED HUMAN LOW-DENSITY-LIPOPROTEIN

Modification of low density lipoprotein (LDL) by free radical oxidatio n renders this molecular complex cytotoxic. Oxidized lipoproteins exis t in vivo in atherosclerotic lesions and in the plasma of diabetic ani mals, suggesting that lipoprotein-induced tissue damage may occur in c ertain diseases. We undertook purification and identification of the m ajor cytotoxin in oxidized LDL. The lipid extract from oxidized LDL wa s subjected to multiple HPLC separations, and the fractions were assay ed for cytotoxicity. Mass spectrometry and nuclear magnetic resonance identified the purified toxin as 7 beta-hydroperoxycholest-5-en-3 beta -ol (7 beta-OOH-Chol). This molecule accounted for approximately 90% o f the cytotoxicity of the lipids of oxidized LDL. We also found 7 beta -00H-Chol in human atherosclerotic lesions from endarterectomy specime ns obtained immediately after excision. These results are consistent w ith the hypothesis that the oxidized LDL present in lesions has the ca pacity to induce cell and tissue injury, leading to progression of the disease and the generation of the necrotic core of the lesion.