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VASCULAR BIOLOGY

Calcium-independent phospholipase A₂ is regulated by a novel protein kinase C in human coronary artery endothelial cells

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

Submitted 29 July 2004 ; accepted in final form 27 September 2004

We demonstrated previously that thrombin stimulation of endothelial cells activates a membrane-associated, Ca²⁺-independent phospholipase A₂ (iPLA₂) that selectively hydrolyzes arachidonylated plasmalogen phospholipids. We report that incubation of human coronary artery endothelial cells (HCAEC) with phorbol 12-myristate 13-acetate (PMA) to activate protein kinase C (PKC) resulted in hydrolysis of cellular phospholipids similar to that observed with thrombin stimulation (0.05 IU/ml; 10 min). Thrombin stimulation resulted in a decrease in arachidonylated plasmenylcholine (2.7 ± 0.1 vs. 5.3 ± 0.4 nmol PO₄/mg of protein) and plasmenylethanolamine (7.5 ± 1.0 vs. 12.0 ± 0.9 nmol PO₄/mg of protein). Incubation with PMA resulted in decreases in arachidonylated plasmenylcholine (3.2 ± 0.3 nmol PO₄/mg of protein) and plasmenylethanolamine (6.0 ± 1.0 nmol PO₄/mg of protein). Incubation of HCAEC with the selective iPLA₂ inhibitor bromoenol lactone (5 mM; 10 min) inhibited accelerated plasmalogen phospholipid hydrolysis in response to both PMA and thrombin stimulation. Incubation of HCAEC with PMA (100 nM; 5 min) resulted in increased arachidonic acid release (7.1 ± 0.3 vs. 1.1 ± 0.1%) and increased production of lysoplasmenylcholine (1.4 ± 0.2 vs. 0.6 ± 0.1 nmol PO₄/mg of protein), similar to the responses observed with thrombin stimulation. Downregulation of PKC by prolonged exposure to PMA (100 nM; 24 h) completely inhibited thrombin-stimulated increases in arachidonic acid release (7.1 ± 0.6 to 0.5 ± 0.1%) and lysoplasmenylcholine production (2.0 ± 0.1 to 0.2 ± 0.1 nmol PO₄/mg of protein). These data suggest that PKC activates iPLA₂ in HCAEC, leading to accelerated plasmalogen phospholipid hydrolysis and increased phospholipid metabolite production.

lysophospholipids; cell signaling; phospholipid metabolism; arachidonic acid

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