Prostaglandins, Leukotrienes and Essential Fatty Acids 77 (2007) 67–77 Review The two faces of the 15-lipoxygenase in atherosclerosis $ Jonas Wittwer, Martin Hersberger Institute of Clinical Chemistry, Center for Integrative Human Physiology, University Hospital Zurich, Raemistrasse 100, CH-8091 Zurich, Swi Received 12 March 2007; received in revised form 12 July 2007; accepted 1 August 2007 Abstract Chronic inflammation plays a major role in atherogenesis and understanding the role of inflammation and its resolution novelapproaches to interfere with atherogenesis. The 15(S)-lipoxygenase (15-LOX) plays a janus-role in inflammation with pro- inflammatory and anti-inflammatory effects in cell cultures and primary cells and even opposite effects on atherosclerosis in two different animal species. There is evidence for a pro-atherosclerotic effect of 15-LOX including the direct contribution to LDL oxidation and to the recruitment of monocytes to the vessel wall, its role in angiotensin II mediated mechanisms and in va smooth muscle cell proliferation. In contrast to the pro-atherosclerotic effects of 15-LOX, there is also a broad line of evide 15-LOX metabolites of arachidonic and linoleic acid have anti-inflammatory effects. The 15-LOX arachidonic acid metabolite 15-HETE inhibits superoxideproduction and polymorphonuclear neutrophil(PMN) migration acrosscytokine-activated endothelium and can be further metabolized to the anti-inflammatory lipoxins. These promote vasorelaxation in the aorta and counteract the action of most other pro-inflammatory factors like leukotrienes and prostanoids. Anti-atherogenic propertie reported for the linoleic acid oxidation product 13-HODE through inhibition of adhesion of several blood cells to the endoth Furthermore, there is evidence that 15-LOX is involved in the metabolism of the long-chain omega-3 fatty acid docosahexa acid (DHA) leading to a family of anti-inflammatory resolvins and protectins. From these cell culture and animal studies th the 15-LOX in human atherosclerosis cannot be predicted. However, recent genetic studies characterized the 15-LOX hapl Caucasians and discovered a functional polymorphism in the human 15-LOX promoter. This will now allow large studies to investigate an association of 15-LOX with coronary artery disease and to answer the question whether 15-LOX is pro- or an atherogenic in humans. r 2007 Elsevier Ltd. All rights reserved. 1. Inflammation in atherosclerosis Atherosclerosis is a multifactorialdiseasethat in- volves chronic inflammationat every stage, from initiation to progression and eventually plaque rupture [1].Soon after the initiation of a hypercholesterolemic diet leukocytes attach to the endothelium as a first sign of inflammation. Extravasation ofthese leukocytes is mediated by sequential adhesive interactions to several cell adhesion molecules present on activated endothelial cells, like the E- and P-selectinsand vascularcell adhesion molecule1 (VCAM-1) [2–4]. VCAM-1 is directly up-regulated by hypercholesterolemia and binds particularly those leukocyte classes that are found in the nascent atheroma, the monocytes and the lymphocytes. Monocytes entering the arterial wall differentiate into macrophagesupon stimulationby growth factors produced by the inflamed intima, like the macrophage colony-stimulating factor [5]. This step is critical for the development of atherosclerosis and is associated with the up-regulation of pattern recognition receptors for innate immunity like the scavenger receptors SR-A and ARTICLE IN PRESS www.elsevier.com/locate/plefa 0952-3278/$ - see front matter r 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.plefa.2007.08.001 Abbreviations: 5-LOX, 15(S)-lipoxygenase; PMN, polymorphonuc- lear neutrophil; DHA, docosahexaenoic acid; OxLDL, oxidized low density lipoproteins; 13-HpODE, 13(S)-hydro(per)oxy-octadecadie- noic acid; 15-HpETE, 15(S)-hydro(per)oxy-eicosatetraenoic acid; 12-HpETE, 12(S)-hydro(per)oxy-eicosatetraenoic acid $ Work related to this review has been supported by the EMDO Stiftung,the Forschungskommission of the University of Zurich, the OPO Stiftung and the Swiss National Science Foundation. Corresponding author. Tel.: +41 44 255 3473; fax:+41 44 255 4590. E-mail address: hmr@ikc.unizh.ch (M. Hersberger).