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.