TY - JOUR T1 - Cytosolic Phospholipase A<sub>2</sub> Activation by the p38 Kinase Inhibitor SB203580 in Rabbit Aortic Smooth Muscle Cells JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 331 LP - 338 VL - 298 IS - 1 AU - S. Fatima AU - Z. Khandekar AU - J.-H. Parmentier AU - Kufait U. Malik Y1 - 2001/07/01 UR - http://jpet.aspetjournals.org/content/298/1/331.abstract N2 - SB203580 [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole] is widely used as a specific inhibitor of p38 mitogen-activated protein kinase (MAPK). Here we report that SB203580, which blocked p38 kinase activation elicited by anisomycin, increased the phosphorylation and activity of cytosolic phospholipase A2 (cPLA2) and arachidonic acid (AA) release in quiescent vascular smooth muscle cells from rabbit aortae. SB203580 also increased the activity of calcium (Ca2+)/camodulin-dependent kinase II (CaMKII) and ERK1/2 MAPK. The increase in CaMKII activity and cPLA2phosphorylation caused by SB203580 was attenuated by CaMKII inhibitor KN-93, indicating involvement of CaMKII in cPLA2phosphorylation by this compound. Since KN-93 also inhibited SB203580-induced ERK1/2 activation, it appears that ERK1/2 activation is also mediated by CaMKII. SB203580-induced cPLA2phosphorylation was inhibited by depletion of Ca2+ from the medium, by the voltage-operated Ca2+ channel blocker nifedipine, and by the calmodulin inhibitor W-7. cPLA2translocation from cytoplasm to the nuclear envelope caused by SB203580 was also inhibited in the absence of extracellular Ca2+. Other p38 kinase inhibitors, SB202190 and PD169316, failed to alter CaMKII, ERK1/2, and cPLA2 activity or cPLA2translocation to the nuclear envelope. These data suggest that SB203580 not only inhibits p38 kinase activity but also increases Ca2+ influx through voltage-sensitive Ca2+channels, which promotes cPLA2 translocation to the nuclear envelope, and by interacting with calmodulin, activates CaMKII and cPLA2 and releases AA. The American Society for Pharmacology and Experimental Therapeutics ER -