INVOLVEMENT OF 15-LIPOXYGENASE IN EARLY STAGES OF ATHEROGENESIS

The arachidonate 15-lipoxygenase which is expressed in atherosclerotic lesions is implicated in the oxidative modification of low density li poproteins during atherogenesis. To obtain experimental in vivo eviden ce for this hypothesis, we analyzed the structure of oxygenated lipids isolated from the aorta of rabbits fed with a cholesterol-rich diet f or different time periods and compared the pattern of oxygenation prod ucts with that isolated from low density lipoproteins treated in vitro with the pure rabbit 15-lipoxygenase and with oxygenated lipids isola ted from advanced human atherosclerotic lesions. In early atherosclero tic lesions (12-wk cholesterol feeding), specific lipoxygenase product s were detected whose structure was similar to those isolated from lip oxygenase-treated low density lipoproteins. The appearance of these pr oducts did coincide with the lipid deposition in the vessel wall. In l ater stages of atherogenesis (26-wk cholesterol feeding) the degree of oxidative modification of the tissue lipids did increase but the shar e of specific lipoxygenase products was significantly lower, suggestin g an increasing overlay of the specific lipoxygenase products by nonen zymatic lipid peroxidation. In advanced human atherosclerotic lesions, large amounts of oxygenation products were detected whose structure s uggests a nonenzymatic origin. These data suggest that the arachidonat e 15-lipoxygenase is of pathophysiological importance during the early stages of atherogenesis. In later stages of plaque development nonenz ymatic lipid peroxidation becomes more relevant.