Chapter 150 - Prostaglandin Mediators

Abstract

Arachidonic acid (AA), a 20-carbon unsaturated fatty acid containing four double bonds, circulates in plasma in both free and esterified forms and is a natural constituent of the phospholipid domain of cell membranes. AA is mobilized for release by phospholipases (PLs) A2, particularly type IV cytosolic (c) PLA2, following its calcium-dependent translocation to the nuclear membrane and the endoplasmic reticulum. Three major groups of enzymes, prostaglandin G/H synthase (PGHS), lipoxygenase, or cytochrome p450, then catalyze the formation of the prostaglandins (PGs) and thromboxane A2 (TxA2), the leukotrienes, or the epoxyeicosatrienoic acids, respectively. Collectively, these products are known as eicosanoids. This chapter focuses on the PGs and TxA2, collectively termed the prostanoids. It begins by describing the cyclooxygenase pathway, which includes COX deletion. Following this, it discusses thromboxane A2 (TxA2), which is a potent vasoconstrictor, mitogen, and platelet activator. Inhibition of platelet TxA2 formation accounts for cardioprotection from aspirin, reflecting the importance of TxA2 as an amplification signal for more potent agonists, such as thrombin and ADP. Analogous to its role in vascular proliferation, TxA2 may also mediate cellular hypertrophy. The cyclooxygenase pathway of arachidonic acid metabolism generates a family of evanescent mediators with wide and varied physiological and pathophysiological actions. Understanding the biological role of the prostanoids requires examination of the biosynthetic pathways that lead to their temporal and tissue-specific generation, together with the array of signaling pathways activated by their multiple receptors.