SYSTEMIC ACTIVATION OF 15-LIPOXYGENASE IN HEART, LUNG, AND VASCULAR TISSUES BY HYPERCHOLESTEROLEMIA - RELATIONSHIP TO LIPOPROTEIN OXIDATIONAND ATHEROGENESIS

There is evidence that oxidized lipoproteins are a major contributing factor in atherosclerosis. 15-lipoxygenase is the principal mammalian enzyme that can oxidize polysaturated fatty acids present in intact li poproteins, and in membrane phospholipids in situ. We, and others, hav e reported previously that levels of the enzyme are increased in aorta s of cholesterol-fed and spontaneously atherosclerotic WHHL rabbits. I n the present study, rabbits were fed an atherogenic diet containing 1 % cholesterol for 14 weeks, and levels of [C-14]arachidonate metaboliz ing enzymes in the excised tissues were measured by HPLC analysis. 15- lipoxygenase levels in heart, aortic adventitia, and lung, but not in liver, were increased up to 100-fold above controls, without major sig nificant changes in prostaglandin endoperoxide synthases or the 5- and 12-lipoxygenases. The induced 15-lipoxygenase activity in the aortic adventitia was approximately 15 times greater than that found in the v essel wall. Hypercholesterolemia and elevated 15-lipoxygenase were ass ociated with a 40% lowering of blood hematocrit. The hemolytic agent p henylhydrazine duplicated the effects of hypercholesterolemia on hemat ocrit, and induced up to 1000-fold increases in 15-lipoxygenase activi ty in tissues within 7 days, The induced 15-lipoxygenase activities in heart and lung were 4 and 8 times greater, respectively, than in reti culocytes, previously the richest known source of the enzyme. Direct m easurements of hemoglobin content also demonstrated that contaminating reticulocytes were not the source of the tissue enzyme. A similar tis sue-specific activation of 15-lipoxygenase was observed in rat heart a nd lung, but also not in liver. It is concluded that the elevated leve l of 15-lipoxygenase activity previously reported in atherosclerotic a orta is symptomatic of a generalized and massive induction of the enzy me in cardio-pulmonary tissues by hypercholesterolemia, which may be r elated to the membrane perturbation and increased hemolysis that is in duced by cholesterol feeding.