Inhibitors of the 5-lipoxygenase pathway in atherosclerosis

The inflammatory environment within the atherosclerotic lesion stimulates the 5-lipoxygenase pathway of arachidonic acid metabolism, leading to the biosynthesis of the potent lipid inflammatory mediators leukotrienes. The present review summarizes the components of this pathway; the enzymes 5-lipoxygenase (5-LO, ALOX5) with its activating protein, FLAP (ALOX5AP), LTA(4) hydrolase and LTC(4) synthase, as well as the receptors for leukotriene B(4) (BLT(1) and BLT(2)) and cysteinyl-leukotrienes (CysLT(1) and CysLT(2)), respectively. Genetic variations within the genes encoding these proteins have been associated with cardiovascular risk. Inhibiting the 5-lipoxygenase pathway through either leukotriene synthesis inhibitors or leukotriene receptor antagonists in experimental models of atherosclerosis has however generated contradictory results. Several inhibitors of the 5-lipoxygenase pathway are now evaluated in clinical trials of patients with cardiovascular disease.