LIPOXYGENASE CONTRIBUTES TO THE OXIDATION OF LIPIDS IN HUMAN ATHEROSCLEROTIC PLAQUES

Oxidized LDL is present in human atherosclerotic lesions, but the mech anisms responsible for oxidation in vivo have not been definitively de monstrated, Circumstantial evidence has implicated the enzyme 15-lipox ygenase as a contributor to the formation of oxidized lipids in this d isease, To assess whether oxidized lipids are indeed formed by the act ion of 15-lipoxygenase on polyunsaturated fatty acids (PUFAs) in vivo, we have used a sensitive and specific method (chiral phase HPLC) to a nalyze the lipid oxidation products present in human atherosclerotic l esions, Human 15-lipoxygenase is an omega-6 lipoxygenase that has prev iously been shown to oxidize esterified PUFA in a stereospecific manne r, forming predominantly cholesteryl hydroperoxy-octadecadienoate (13( S)-HPODE) from cholesteryl linoleate substrate in LDL. This property a llows its activity to be distinguished from nonenzymatic oxidation, wh ich results in the Formation of equal quantities of the S and R stereo isomers of the same oxidation product, A total of 80 specimens of huma n atherosclerotic plaque were analyzed. Esterified, oxidized linoleate was purified from human atherosclerotic lesions and from LDL oxidized by copper, acid the chirality of these oxidation products was compare d, There was significantly greater stereospecificity of oxidation in t he oxidized linoleate from human atherosclerotic lesions. Even greater stereospecificity was detected in the HPODE derived from cholesteryl ester, purified from human lesions, Cholesteryl HPODE is the primary o xidation product from cholesteryl linoleate, the major esterified PUFA that accumulates in atherosclerotic vessels, Cholesteryl HPODE and it s reduced form, cholesteryl hydroxy-octadecadienoate, mere detected in all lesions analyzed. Neither the stereospecificity of oxidation nor the percentage of available substrate oxidized to primary oxidation pr oducts was correlated with the stage of disease of the lesions examine d, We conclude that 15-lipoxygenase contributes to the formation of ox idized lipids in human atherosclerotic lesions.