Cytosolic phospholipase A2 activation by the p38 kinase inhibitor SB203580 in rabbit aortic smooth muscle cells.
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 cPLA2 phosphorylation caused by SB203580 was attenuated by CaMKII inhibitor KN-93, indicating involvement of CaMKII in cPLA2 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 cPLA2 phosphorylation was inhibited by depletion of Ca2+ from the medium, by the voltage-operated Ca2+ channel blocker nifedipine, and by the calmodulin inhibitor W-7. cPLA2 translocation 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 cPLA2 translocation 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.
Fatima
S
S
Department of Pharmacology, University of Tennessee, Memphis, Tennessee 38163, USA.
Khandekar
Z
Z
Parmentier
J H
JH
Malik
K U
KU
D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D054513:Group IV Phospholipases A2; D007093:Imidazoles / Q000494:pharmacology*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010741:Phospholipases A / Q000187:drug effects* / Q000378:metabolism; D054467:Phospholipases A2; D010766:Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology*; D011817:Rabbits; D048051:p38 Mitogen-Activated Protein Kinases
D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D010741:Phospholipases A; D054513:Group IV Phospholipases A2; D054467:Phospholipases A2; C093642:SB 203580