SYSTEMIC ACTIVATION OF 15-LIPOXYGENASE IN HEART, LUNG, AND VASCULAR TISSUES BY HYPERCHOLESTEROLEMIA - RELATIONSHIP TO LIPOPROTEIN OXIDATION AND 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 lipoproteins, and in membrane phospholipids in situ. We, and others, have reported previously that levels of the enzyme are increased in aortas of cholesterol-fed and spontaneously atherosclerotic WHHL rabbits. In the present study, rabbits were fed an atherogenic diet containing 1% cholesterol for 14 weeks, and levels of [C-14]arachidonate metabolizing 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 significant 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 vessel wall. Hypercholesterolemia and elevated 15-lipoxygenase were associated with a 40% lowering of blood hematocrit. The hemolytic agent phenylhydrazine duplicated the effects of hypercholesterolemia on hematocrit, and induced up to 1000-fold increases in 15-lipoxygenase activity in tissues within 7 days, The induced 15-lipoxygenase activities in heart and lung were 4 and 8 times greater, respectively, than in reticulocytes, previously the richest known source of the enzyme. Direct measurements of hemoglobin content also demonstrated that contaminating reticulocytes were not the source of the tissue enzyme. A similar tissue-specific activation of 15-lipoxygenase was observed in rat heart and lung, but also not in liver. It is concluded that the elevated level of 15-lipoxygenase activity previously reported in atherosclerotic aorta is symptomatic of a generalized and massive induction of the enzyme in cardio-pulmonary tissues by hypercholesterolemia, which may be related to the membrane perturbation and increased hemolysis that is induced by cholesterol feeding.