A 40-year-old woman presented to her doctor with a 6-month history of increasing shortness of breath. This was associated with poor appetite and ankle swelling. On physical examination, she had elevated jugular venous distention, a soft tricuspid regurgitation murmur, clear lungs, and mild peripheral edema. An echocardiogram revealed tricuspid regurgitation, severely elevated pulmonary pressures, and right ventricular enlargement. Cardiac catheterization confirmed the severely elevated pulmonary pressures. She was commenced on appropriate therapies. Which of the eicosanoid agonists have been demonstrated to reduce both morbidity and mortality in patients with such a diagnosis? What are the modes of action?
The eicosanoids are oxygenation (oxidation) products of polyunsaturated 20-carbon long-chain fatty acids (eicosa, Greek for “twenty”).* They are ubiquitous in the animal kingdom and are also found in a variety of plants. They constitute a very large family of compounds that are highly potent and display an extraordinarily wide spectrum of important biologic activities. Thus, the eicosanoid ligands, their specific receptors, their synthetic enzymes and inhibitors, and their plant and fish oil precursors, are therapeutic targets for a growing list of conditions.
ARACHIDONIC ACID & OTHER POLYUNSATURATED PRECURSORS
Arachidonic acid (AA) (5,8,11,14-eicosatetraenoic acid), the most abundant of the eicosanoid precursors, is a 20-carbon (C20) polyunsaturated fatty acid containing four double bonds (C20:4(5,8,11,14)). Linoleic acid, an essential fatty acid, is converted to linolenic acid, followed by conversion to AA. The first double bond in AA occurs at 6 carbons from the methyl end, defining AA as an omega-6 fatty acid (C20:4(ω–6) or C20:4-6). AA must first be released or mobilized from the sn-2 position of membrane phospholipids by one or more lipases of the phospholipase A2 (PLA2) type (Figure 18–1) for eicosanoid synthesis to occur. The phospholipase A2 superfamily consists of over 30 isoforms classified into several families, contributing to arachidonate release from membrane lipids. The major two families are cytosolic PLA2 (cPLA2) and secretory PLA2 (sPLA2), both of which are calcium-dependent. Others include calcium-independent PLA2 (iPLA2); platelet-activating factor acetylhydrolase (PAF-AH); lysosomal PLA2 (LPLA2); PLA/acyltransferase (PLAAT); and α/β hydrolase (ABHD). Chemical and physical stimuli activate the Ca2+-dependent translocation of cPLA2 to the plasma membrane, where it releases arachidonate for metabolism to eicosanoids. While cPLA2 dominates in the acute release of AA, inducible sPLA2 contributes under conditions of sustained or intense stimulation of AA production. In contrast, under non-stimulated conditions, AA liberated by iPLA2 is reincorporated into cell membranes, so there is negligible eicosanoid biosynthesis. AA can also be released from phospholipase C-generated diacylglycerol esters by the action of diacylglycerol and monoacylglycerol lipases.
Pathways of arachidonic acid (AA) release and metabolism.