15-lipoxygenase-1 in the vasculature: expanding roles in angiogenesis.

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 12hydroperoxy-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 15LO-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 and in humans.3,5 Moreover, its induction has been observed in human monocytes, macrophages, and human lung carcinoma cell line A549 by stimulation with interleukin (IL)-4 or IL-13.3 The level of 15-LO-1 appears to be altered during the tumor development.4 Such expression profiles in a wide variety of cells, together with its enzymatic potential to produce reactive oxygen species and lipid hydroperoxides, have raised the possibility that 15-LO-1 and its products may be crucially involved in many pathological conditions, such as asthma, inflammation, atherogenesis, and carcinogenesis. However, the evidence to date is controversial if not contradictory, and the underlying molecular mechanisms of 15LO-1 in certain disease processes remain far from clear. The biological relevance of 15-LO-1 in the vascular system has been widely explored and supported by its expression in vascular cells and the results from functional studies. Specifically, expression and function of 15-LO-1 have been studied in endothelial cells (ECs), smooth muscle cells, and monocytes as well as atherosclerotic animal models, and 15-LO-1 has been shown to play active roles in vascular remodeling and the progression of atherosclerosis.2,3,5,7,8 Although the directly relevant data are limited, 15-LO-1 has also been implicated for its role in angiogenesis. In this issue of Circulation Research, Viita et al assign a new role for 15-LO-1 as a regulator of angiogenesis by demonstrating its antiangiogenic action in rabbit skeletal muscle system.9 They have previously developed an adenovirus-mediated gene transfer method into the rabbit hindlimb model and shown that vascular endothelial growth factor (VEGF)-A induces strong angiogenic effects in skeletal muscles.10 In this study, they show that coadministration of 15-LO-1 significantly decreases all angiogenic effects induced by VEGF-A and placental growth factor (PlGF), including capillary perfusion, vascular permeability, vasodilatation, and the increase in capillary number. However, the role of 15-LO-1 in angiogenesis still remains controversial and requires careful scrutiny. Several studies in tumor models have shown that the enzyme and its products could promote or inhibit neovascularization. The PC-3 human prostate cancer cell line, which overexpresses 15-LO-1, secretes high levels of VEGF and enhances tumor growth and angiogenesis as compared with the parental PC-3 cell lines.11 In contrast, angiogenesis and tumor formation in 2 xenograft models is inhibited in transgenic mice overexpressing 15LO-1 in ECs under the control of preproendothelin promoter.12 The angiogenic process is complex and occurs in multiple steps coordinated by integrated action of various cells including ECs and their surrounding cells. Considering the complexity of angiogenic process, elucidation of the precise mechanism of action of 15-LO-1 in angiogenesis probably requires evaluating signaling and secondary chemThe opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Department of Structural Analysis (N.M.), National Cardiovascular Center Research Institute, Osaka, Japan; and Department of Biochemistry (Y.-G.K.), College of Sciences, Yonsei University, Seoul, Korea. Correspondence to Young-Guen Kwon, PhD, Department of Biochemistry, College of Sciences, Yonsei University, Seoul 120-749, Republic of Korea. E-mail [email protected] (Circ Res. 2008;102:143-145.) © 2008 American Heart Association, Inc.