5-Lipoxygenase-Derived Leukotrienes

A therogenesis is now viewed as the outcome of hypercholesterolemia in combination with inflammation of the vessel wall; an intertwined sequence of events leads to fatty streaks, which may develop to atherosclerosis. 1 Several recent studies have implicated lipoxygenases in this process.Mammalian lipoxygenases have two principal functions.2 One is to modify membranes by peroxidation reactions; 12/15-lipoxygenases (12/15-LOs, in homo 15-LO type 1) is typically connected with this function.The other is to produce signaling lipid mediators which exert effects via G protein-coupled plasma membrane-bound receptors; maybe the best example is 5-lipoxygenase (5LO) and the leukotrienes.3,4 Accordingly, lipoxygenases can in principle contribute to the pathophysiology of atherosclerosis in two ways: by LDL oxidation and by biosynthesis of proinflammatory leukotrienes.The first articles indicating a role for 12/15-LO in oxidative modification of LDL appeared Ϸ10 years ago, 5,6 for a recent review discussing pro-and anti-atherogenic effects of 12/15-LO, see the article by Funk and Cyrus.7 In the June issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Kühn et al 8 present data showing that mutations in 5LO occurring in atherosclerosis-resistant CAST/CON6 mice reduces the activity of 5LO in vitro.Here, recent findings which support of a role for 5LO and leukotrienes in atherosclerotic inflammation are discussed.