Catalytic features, regulation and function of myocardial phospholipase A₂

Phospholipase A₂ (PLA₂) catalyzes the hydrolysis of sn-2 fatty acids from membranephospholipids resulting in the production of several biologically active phospholipid metabolites such as lysophospholipids, arachidonic acid, eicosanoids and platelet-activating factor. The majority of myocardial PLA₂ activity is membrane-associated and does not require Ca²⁺ for activity (iPLA₂). Myocardial iPLA₂ demonstrates unique characteristics when compared to other PLA₂ isoforms described previously, including a selectivity for plasmalogen phospholipids and resistance to inhibition by methyl arachidonyl fluorophosphonate. Activation of myocardial iPLA₂ results in the production of lysoplasmenylcholine and arachidonic acid, both of which can change the electrophysiologic properties of the myocardium. Arachidonic acid can modulate ion channel activity via protein kinase C activation and has been demonstrated to decrease gap junctional conductance. Lysoplasmenylcholine directly produces action potential derangements and alters calcium cycling in cardiac myocytes. Thus, inhibition of iPLA₂ activity to block production of phospholipid metabolites that mediate pathologic changes in the myocardium would be of considerable benefit. However, there are situations where inhibition of PLA₂ activity would be detrimental to the myocardium, in particular if iPLA₂ acts as a phospholipid repair enzyme following oxidative damage. Although little is known regarding the function of cPLA₂ orsPLA₂ inthe myocardium, it is possible that they may be important for signal transduction or may modulate the activity of iPLA₂.