15-Lipoxygenase-1 in the Vasculature

Abstract

See related article, pages 177–184 Lipoxygenases (LOs) constitute a heterogeneous family of enzymes that catalyze the stereoselective dioxygenation of polyunsaturated fatty acids to their corresponding hydroperoxy derivatives.1,2 In mammals, LOs are categorized with respect to their positional specificity of arachidonic acid oxygenation into 5-, 8-, 12-, and 15-LOs.1–3 These enzymes induce structural and metabolic changes in cells during a wide variety of physiological and pathological processes, such as differentiation, carcinogenesis, inflammation, and atherogenesis. Accumulating studies have suggested diverse and opposing roles for the various LO pathways in the pathogenesis of human diseases, particularly cancer and atherosclerosis.2–5 Consistent with the existence of multiple isoforms of LOs, a variety of intermediate and end products of arachidonic acids are found in various cell types, and they in turn activate diverse signaling cascades, resulting in diverse outcomes. Therefore, sophisticated understanding of the expression pattern of individual isozymes in the target cells and biological actions of the corresponding metabolites should be prerequisite for predicting their roles in disease processes. Among the 4 mammalian LO subfamilies, 15-lipoxygenase-1 (also known as 12/15-lipoxygenase in mice) catalyzes the transformation of free arachidonic acid to 12-hydroperoxy-eicosatetraenoic acid and15-hydroperoxyeicosatetraenoic acid and the transformation of linoleic acid to 13-hydroperoxyoctadecadienoic acid (13-HPODE) (the reduced product is 13-HODE).3,4 Both human 15-LO-1 and mouse 12/15-LO enzymes also metabolize more complex lipids, including phospholipids, cholesterol esters, and plasma lipoproteins. 15-LO-1 was considered initially to be the reticulocyte LO that can react with mitochondrial membrane lipids,6 but subsequently, a constitutive expression of 15-LO-1 has been reported in various types of cells, such as immature red blood cells, eosinophils, and airway epithelial cells.3 In addition, the eicosanoid products of 12/15-LO have been detected in vascular cells, and 15-LO-1 protein has been shown to be localized to aortic atherosclerotic lesions in rabbits …