The role of lipoxygenase-isoforms in atherogenesis

Abstract

Lipoxygenases (LOXs) form a heterogeneous family of lipid-peroxidizing enzymes, and several LOX-isoforms (12/15-LOX, 5-LOX) have been implicated in atherogenesis. However, the precise role of these enzymes is still a matter of discussion. 12/15-LOXs are capable of oxidizing lipoproteins (low-density lipoprotein (LDL), high-density lipoprotein (HDL)) to atherogenic forms, and functional inactivation of this enzyme in murine atherosclerosis models slows down lesion formation. In contrast, rabbits that overexpress this enzyme were protected from lesion formation when fed a lipid-rich diet. To contribute to this discussion, we recently investigated the impact of 12/15-LOX overexpression on in vitro foam cell formation. When 12/15-LOX-transfected J774 cells were incubated in culture with modified LDL, we found that intracellular lipid deposition was reduced in the transfected cells when compared with the corresponding control transfectants. This paper briefly summarizes the current status of knowledge on the biological activity of different LOX-isoforms in atherogenesis and will also provide novel experimental data characterizing the role of 12/15-LOX in cellular LDL modification and for in vitro foam cell formation.

12/15-lipoxygenase–mediated enzymatic lipid oxidation regulates DC maturation and function

“…Both enzymes oxygenate free and esterified polyunsaturated fatty acids (3). 12/15-LO has been shown to be expressed in foam cells within the atherosclerotic plaque and has been implicated in the oxidation of LDL particles and generation of proinflammatory lipid oxidation products that drive vascular inflammation and the development of atherosclerotic plaques (4,5). However, the physiological role of this enzyme is still incompletely understood.…”

Mouse Models of Experimental Atherosclerosis as a Tool for Checking a Putative Anti-Atherogenic Action of Drugs

“…In 2002 Mehrabian et al identified the 5-LO as a crucial enzyme, contributing to atherosclerosis susceptibility in mice (Mehrabian et al, 2002;. This observation, after a long pause (De Caterina R et al, 1988) has again focused the attention of researchers on the role of leukotrienes in the pathogenesis of atherosclerotic plaque (Radmark, 2003;Kuhn et al, 2005;Kuhn H, 2005;Lotzer et al, 2005;Back & Hansson, 2006;Radmark & Samuelsson, 2007). Therefore, the speculations have been risen that anti-asthmatic drugs could have beneficial effects on atherogenesis (Spanbroek & Habenicht, 2003;Wickelgren, 2004;Funk, 2005;Back, 2006).…”

15-Lipoxygenase-1 in the Vasculature

“…Accumulating studies have suggested diverse and opposing roles for the various LO pathways in the pathogenesis of human diseases, particularly cancer and atherosclerosis. [2][3][4][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.…”

“…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.…”

“…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.…”