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CARDIOVASCULAR

Inhibition of Platelet-Activating Factor (PAF) Acetylhydrolase by Methyl Arachidonyl Fluorophosphonate Potentiates PAF Synthesis in Thrombin-Stimulated Human Coronary Artery Endothelial Cells

Department of Pathology, St. Louis University School of Medicine, St. Louis, Missouri

We have previously demonstrated that thrombin stimulation of endothelial cells results in increased membrane-associated, Ca²⁺-independent phospholipase A₂ (iPLA₂) activity, accelerated hydrolysis of membrane plasmalogen phospholipids, and production of several biologically active phospholipid metabolites, including prostacyclin and platelet-activating factor (PAF) that is abolished by pretreatment with the iPLA₂-selective inhibitor bromoenol lactone. This study was designed to further investigate the role of alternative PLA₂ inhibitors, including methyl arachidonyl fluorophosphonate (MAFP, an inhibitor of cytosolic PLA₂ isoforms), on phospholipid turnover and PAF production from thrombin-stimulated human coronary artery endothelial cells (HCAECs). Paradoxically, pretreatment of HCAEC with MAFP (5–25 µM) resulted in a significant increase in PAF production in both unstimulated and thrombin-stimulated cells that was found to be a direct result of inhibition of PAF acetylhydrolase (PAF-AH) activity. Pretreatment with MAFP did not significantly inhibit HCAEC PLA₂ activity, possibly due to the localization of PLA₂ activity in the membrane fraction rather than the cytosol. Bromoenol lactone did not inhibit PAF-AH activity, even at concentrations as high as 20 µM. We conclude that MAFP augments thrombin-stimulated PAF production by inhibition of PAF catabolism without affecting membrane-associated iPLA₂ activity.

Address correspondence to: Dr. Jane McHowat, Department of Pathology, St. Louis University School of Medicine, 1402 S. Grand Blvd., St. Louis, MO 63104. E-mail: mchowatj{at}slucare1.sluh.edu

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