sPLA(2) cooperates with cPLA(2)alpha to regulate prostacyclin synthesis in human endothelial cells.
The first step in prostacyclin (PGI(2)) synthesis involves the generation of arachidonic acid (AA) from membrane phospholipids mediated by the 85 kDa cytosolic phospholipase A(2) (cPLA(2)alpha). The current study examined the effects of secretory PLA(2)s (sPLA(2)s) on PGI(2) production by human umbilical vein endothelial cells (HUVEC). We demonstrate that exposure of HUVEC to sPLA(2) dose- and time-dependently enhances AA release and PGI(2) generation. sPLA(2)-stimulated AA mobilisation was blocked by AACOCF(3), an inhibitor of cPLA(2)alpha, suggesting cross-talk between the two classes of PLA(2). sPLA(2) induced the phosphorylation of cPLA(2)alpha and enhanced the phosphorylation states of p42/44(mapk), p38(mapk), and JNK, concomitant with elevated AA and PGI(2) release. The MEK inhibitor PD98059 attenuated sPLA(2)-stimulated cPLA(2)alpha phosphorylation and PGI(2) release. These data show that sPLA(2) cooperates with cPLA(2)alpha in a MAPK-dependent manner to regulate PGI(2) generation and suggests that cross-talk between sPLA(2) and cPLA(2)alpha is a physiologically important mechanism for enhancing prostanoid production in endothelial cells.
Houliston
R A
RA
Department of Veterinary Basic Sciences, The Royal Veterinary College, University of London, Royal College Street, London NW1 0TU, United Kingdom. rhoulist@rvc.ac.uk
Wheeler-Jones
C P
CP
D016718:Arachidonic Acid / Q000378:metabolism; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D011464:Epoprostenol / Q000096:biosynthesis*; D005419:Flavonoids / Q000494:pharmacology; D054501:Group II Phospholipases A2; D054513:Group IV Phospholipases A2; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013997:Time Factors
D016895:Culture Media, Serum-Free; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007527:Isoenzymes; D016718:Arachidonic Acid; D011464:Epoprostenol; D020928:Mitogen-Activated Protein Kinases; D010741:Phospholipases A; D054501:Group II Phospholipases A2; D054513:Group IV Phospholipases A2; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one