Prostaglandin production in human coronary artery endothelial cells is modulated differentially by selective phospholipase A2 inhibitors.

Abstract: Atherosclerotic plaque formation is a dynamic process involving repeated injury and inflammation of the endothelium. We have demonstrated previously that thrombin and tryptase stimulation of human coronary artery endothelial cells (HCAEC) leads to increased phospholipase A₂ (PLA₂) activity and generation of membrane phospholipid derived inflammatory metabolites, including eicosanoids and platelet activating factor. Thus, our hypothesis is that selective PLA₂ inhibitors have therapeutic potential as anti-inflammatory agents. Stimulation of confluent HCAEC monolayers with thrombin or tryptase resulted in a concentration and time-dependent increase in both prostaglandin E₂ (PGE₂) and prostacyclin (PGI₂) production. Pretreatment with PX-18 to inhibit secretory PLA₂ or BEL to inhibit calcium-independent PLA₂ prior to thrombin or tryptase stimulation resulted in a significant inhibition of both PGI₂ and PGE₂ release. However, pretreatment with methyl arachidonyl fluorophosphonate (MAFP), a widely used inhibitor of cytosolic PLA₂ isoforms, resulted in a significant potentiation of both thrombin and tryptase stimulated PGI₂ and PGE₂ release as a consequence of increased free arachidonic acid production. We conclude that the use of selective PLA₂ inhibitors may be of therapeutic benefit in the development and progression of atherosclerosis, however, the development of such an agent requires rigorous screening. [Copyright &y& Elsevier]