Synthesis of prostaglandins and thromboxane B2 by cholesterol-fed rabbits

Abstract

Alterations in the synthesis of thromboxane A2 (TxA2) and prostacyclin have been implicated in the development of atherosclerosis. We measured the amounts of the degradation products of these substances, TxB2 and 6-oxo-prostaglandin F1α (6-oxo-PGF1α, respectively, as well as PGE2, that were synthesized by slices and the luminal surfaces of aortas from rabbits fed either a control diet or a diet supplemented with cholesterol and peanut oil. For these studies, we developed conditions that were designed to minimize the autoinactivation of cyclooxygenase during removal and preparation of the tissue. Pretreatment of aortas with a medium containing ibuprofen and EDTA resulted in an approximately twofold increase in 6-oxo-PGF1α production upon subsequent incubation. Despite the increased lipid peroxidation associated with atherosclerotic lesions, we observed no changes in either aortic 6-oxo-PGF1α production or in the levels of its major urinary metabolite, 2,3-dinor-6-oxo-PGF1α, after as long as 15 weeks of dietary supplementation with cholesterol and peanut oil. Similarly, synthesis of PGE2 by aortic slices and the aortic lumen was the same in cholesterol-fed and control rabbits. In contrast to aortic 6-oxo-PGF1α and PGE2 synthesis, there was a dramatic 10-fold increase in TxB2 released from slices of thoracic aorta after 15 weeks on the atherogenic diet. This was much greater than the approximately twofold increase in the synthesis of TxB2 by the luminal surface of the thoracic aorta, suggesting that the primary site of TxB2 synthesis in the aorta is in the inner part of the blood vessel. Slices of pulmonary artery released more TxB2, 6-oxo-PGF1α, and PGE2 than did slices from the aortic arch or the middle section of the thoracic aorta in control rabbits. However, the aortic arch was the major site of TxB2 production in hypercholesterolemic rabbits. It is possible that aortic TxA2, could contribute to the development of atherosclerosis due to its potent effects on platelets.