112 - Endothelial Eicosanoids

Summary

Eicosanoids comprise a large array of small-molecular-weight compounds that are synthesized in almost all mammalian cells from an unsaturated fatty acid, arachidonic acid (AA), chemically known as eicosatetraenoic acid. Eicosanoids are not stored in cells, but are synthesized in cells in response to stimuli. Elevated intracellular calcium and activation of protein kinase C (PKC) as the result of cell activation represent two key signaling pathways that initiate eicosanoid production. These signaling molecules activate a group of phospholipase A₂ (PLA₂), most notably the cytosolic PLA₂, that catalyze the release of AA from membrane phospholipids (1,2). AA is metabolized to form eicosanoids by many enzymes, now classified into three enzymatic pathways: (a) cyclooxygenase (COX), (b) lipoxygenase (LOX), and (c) cytochrome P450 (CYP) (Figure 112.1). The COX pathway converts AA into classic prostaglandins (PG), namely prostacyclin (also known as PGI₂) and thromboxane A₂ (TXA₂). The LOX pathway is responsible for producing leukotrienes (LT) and 5-, 12-, and 15-hydroxyeicosatetraenoic acid (HETE) (3,4). The CYP pathway generates diverse epoxy eicosatetraenoic acid (EET) and dihydroxy eicosatetraenoic acid (di-HETE) products (5).

Intracellular eicosanoids are released into extracellular milieu, where they act in an autocrine or paracrine manner. They bind a specific family of membrane eicosanoid receptors and induce diverse cellular activities via selective signaling pathways (6). Evidence is emerging that certain eicosanoids that are produced in the cell bind directly to intracellular receptors, thereby eliciting their cellular actions. Eicosanoids possess multiple, diverse biological actions that regulate and mediate the physiological functions of many organs. They play major pathophysiological roles in human diseases including cardiovascular disorders, asthma, and cancer (7–9).