Lipoxygenases in the cardiovascular system.

Abstract

Lipoxygenases (LOXs) are nonheme iron-containing enzymes that catalyze dioxygenation of free or esterified polyenoic fatty acids to the corresponding hydroperoxides.1 Although LOXs in plants have been known for almost a century, the first mammalian LOXs were not discovered until the mid 1970s.2 In 1984 a 15-LOX activity was described in human atherosclerotic lesions,3 and since then the number of reports connecting LOXs to the cardiovascular system has steadily increased.4–12 Cardiovascular research requires suitable animal models, with rats, mice, and rabbits as the preferred species. Unfortunately, concerning LOXs, there are profound differences between these animal species and humans. In humans there are 6 functional LOX genes that encode for separate LOX isoforms,13 but only 3 of them (5-LOX, platelet-type 12-LOX, reticulocyte-type 15-LOX) appear to be important for vascular disorders. Except for the 5-LOX gene (mapped to chromosome 10), all human LOX genes are located on the short arm of chromosome 17. In mice, however, there are 7 functional LOX genes, and they were mapped to synthetic regions of the murine genome.13 In contrast to humans, there is no reticulocyte-type 15-LOX in mice, but the leukocyte-type 12-LOX appears to be its functional equivalent. This difference needs to be considered if the enzymes exhibit their biological activities via the formation of bioactive arachidonic acid oxygenation products (12S-HETE in mice versus 15S-HETE in humans). In rabbits, the situation is even more complex. Here, 2 separate genes have been discovered encoding for a reticulocyte-type 15-LOX and a leukocyte-type 12-LOX.14 Expression of the 2 genes is under the control of distinct regulatory sequences, and their tissue-specific …