Cytosolic phospholipase A(2) activation by the p38 kinase inhibitor SB203580 in rabbit aortic smooth muscle cells

S8203580 [4-(4-fluorophenyl)-2-(4-melhylsulfinylphenyl)-5-(4- pyridyl)1H-im idazote] is widely used as a specific inhibitor of p38 mitogen-activated pr otein kinase (MAPK). Here we report that SB203580, which blocked p38 kinase activation elicited by anisomycin, increased the phosphorylation and activ ity of cytosolic phospholipase A(2)(cPLA(2)) and arachidonic acid (AA) rele ase 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 cPLA(2) phos phorylation caused by SB203580 was attenuated by CaMKII inhibitor KN-93, in dicating involvement of CaMKII in cPLA(2) phosphorylation 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 cPLA(2) phosphorylation was inhibited by depletion of Ca2+ from the medium, by the voltage-operated Ca2+ channel blocker nifedipine, and by the calmodulin in hibitor W-7. cPLA(2) translocation from cytoplasm to the nuclear envelope c aused 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 cPLA(2) activity or cPLA(2) translocation to the nuclear envel ope. These data suggest that S8203580 not only inhibits p38 kinase activity but also increases Ca2+ influx through voltage-sensitive Ca2+ channels, wh ich promotes cPLA(2) translocation to the nuclear envelope, and by interact ing with calmodulin, activates CaMKII and cPLA(2) and releases AA.