A hyperresponsive 15-lipoxygenase phenotype in rabbit and human populations: relationship to atherosclerosis.

It i s generally recognized that high levels of low density lipoprotein are associated with the development of atherosclerosis A considerable body of evidence has accumulated to indicate that a critical step in atherogenesis, i s oxidation of LDL, and that circumstances that promote oxidation of LDL may constitute a major risk-factor for atherosclerosis (1) A major catalyst of lipoprotein oxidation in vivo i s the enzyme 15-ltpoxygenase This enzyme can oxidize polyunsaturated fatty acids present in intact lipids and lipoproteins Steinberg has estimated that up to 75% of the oxidative damage to LDL by macrophages i s caused by 15-lipoxygenase Atherosclerotic lesions in rabbit aorta contain increased 15-lipoxygenase activity (2) and oxidized LDL epitopes colocalize with immunoreactive 154ipoxygenase protein in the lesions (1) Hypercholesterolemia i s associated with increased 15lipoxygenase in a number of rabbit tissues particularly lung where elevations of several hundred fold were observed in some animals (3) Systemic induction of the 154ipoxygenase was duplicated by administration of the cytolytic agent phenylhydrazine, and was accompanied by systemic lipoprotein oxidation detected by accumulation of the characteristic oxidation products 15-HETE and 13-HODE in the serum lipids The phenomenon of a hyperresponsive 15-lipoxygenase phenotype was encountered during analysis of vascular tissues in hypercholesterolemic rabbits Of a total of 32 rabbits, 7 animals (21 %) were hyperoxidizers with elevations of 15-lipoxygenase in the range of 150-250 units/g, compared to a normal level of 0 5-1 units/g 10 Rabbits were in the medium range (5-25 units/@ and 15 were in the low range (1-5 unitdg) In studies with human blood donors, similar elevations in 1 5-lipoxygenase activity in polymorphonuclear leukocytes, have been observed in response to cytolytic concentrations of drugs such as ibuprofen (4,5) The 15-lipoxygenase responses of PMN’s from a group of 20 subjects were therefore analyzed for evidence of a hyperoxidizer phenotype (Table 1)