Leukotrienes in Cardiovascular Diseases

Cysteinyl-Ieukotrienes (cys-LTs, LTC4, LTD4 and LTE4) are potent lipid mediators, resulting from the oxidative metabolism of arachidonic acid through the 5-lipoxygenase (5-LO) pathway. They are able to affect all major components of the cardiovascular system: they can constrict small and large vessels, modify cardiac and coronary functions, influence the microcirculation and contribute to the manifesta­ tions of ischaemia/reperfusion injuryl.2. Furthermore cys-LTs are able to induce profound modification of vascula~ permeability, leading to oedema formation 3 . Cys-LT biosynthesis is dependent on the activity of the 5-LO enzyme, a single protein possessing the dioxygenase activity necessary for the synthesis of 5-hydroperoxy eicosatetraenoic acid (5-HpETE), and the epoxygenase activity lead­ ing to leukotriene A4 (LTA4)4. This unstable allylic epoxide can be further converted by two different enzymes: LTA4 hydrolase, catalysing the conversion into leukotriene B4 (LTB4), and leukotriene C4 synthase, responsible for the specific introduction of a molecule of glutathione on LTA4 resulting in the formation of leukotriene C4 (LTC4)5. The distribution of these secondary enzymes characterizes the final product of 5-LO activation in different cellular species: neutrophils generate predominantly LTB4, a compound with very potent chemo-attractant activities6 , while eosinophils and mast­ cells7 .8 show preferential production of cys-LT. Recently it has been shown that the secondary enzymes (i.e. LTA4 hydrolase and LTC4 synthase) are also expressed by cells which do not contain the primary oxidative enzyme, (5-LO). Erythrocytes, platelets, and endothelial cells (EC) are indeed able to take up the unstable metabolic intermediate LTA4 and convert it into LTB4 (erythrocytes) or LTC4 (EC and platelets). It has been known for many years that neutrophils and mast cells, which possess a very active 5-LO, release extracellularly substantial amounts of unmetabolized LTA 4 . Taken together these observations led to experiments proving the cooperation of dif­ ferent cells for the biosynthesis of biologically active leukotrienes 9-13. This type of biosynthetic reaction involving the cooperation of different cell types has been named transcellular synthesis, and it supports the hypothesis that the cellular environment (cell-cell interactions) may affect both quantitatively and qualitatively the profile of metabolites resulting from the activation of 5-LO-bearing cells l4.