Cysteinyl-Leukotrienes in Cerebrovascular Disease

Abstract

Although the initial interest in the field of leukotriene (LT) research was focused on their potent bronchoconstrictive effects, subsequent studies have suggested LTs as key mediators in several inflammatory diseases. Genetic variations within the enzymes transforming arachidonic acid into LTs (Figure) have for example been associated with atherosclerosis and an increased risk of cardiovascular events.1 Figure Metabolism of arachidonic acid into leukotrienes (LTs) by 5-lipoxygenase (5-LO), 5-LO activating protein (FLAP), LTA4 hydrolase (LTA4H), and LTC4 synthase (LTC4S). Cysteinyl-LTs (LTC4, LTD4, LTE4) activate CysLT receptors, which can be targeted by antiasthmatic CysLT1 receptor antagonists. Inset shows the 5 exons (I-V) of the LTC4S gene and its 5′-flanking untranscribed region (UTR). The 2 reported single nucleotide polymorphisms (SNP) are located at 444 and 1072 bp upstream, respectively. The −444 A to C substitution has been associated with increased LTC4 synthesis in eosinophils,6 aspirin intolerant asthma,5 increased risk for coronary calcium,10 increased carotid artery intima media thickness (IMT),10 and a decreased risk of ischemic cerebrovascular events.4 See accompanying article on page 990 Leukotriene C4 synthase (LTC4S; Figure) is a microsomal glutathione-S-transferase (mGST), which conjugates LTA4 with glutathione.2 The product, LTC4, shares its following enzymatic steps with glutathione to …