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Research ArticleCELLULAR AND MOLECULAR

Cytosolic Phospholipase A2 Activation by the p38 Kinase Inhibitor SB203580 in Rabbit Aortic Smooth Muscle Cells

S. Fatima, Z. Khandekar, J.-H. Parmentier and Kufait U. Malik
Journal of Pharmacology and Experimental Therapeutics July 2001, 298 (1) 331-338;
S. Fatima
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Z. Khandekar
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J.-H. Parmentier
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Kufait U. Malik
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Abstract

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.

Footnotes

  • This work was supported by National Institutes of Health Grant 19134-26 from the Heart, Lung and Blood Institute. S.F. and J.H.P. are Postdoctoral Fellows of the American Heart Association, Southeast Affiliate; Z.K. is the Postdoctoral Fellow of Research Training in Connective Tissue Disease, Grant NIH-NIAMS 07317-22.

  • Abbreviations:
    MAPK
    mitogen-activated protein kinase
    MEK
    MAPK kinase
    cPLA2
    cytosolic phospholipase A2
    ERK
    extracellular signal-regulated kinase
    CaMKII
    Ca2+/calmodulin-dependent protein kinase II
    AA
    arachidonic acid
    VSMC
    vascular smooth muscle cell
    NE
    norepinephrine
    ECL
    enhanced chemiluminescence
    • Received December 4, 2000.
    • Accepted March 13, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 298 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 298, Issue 1
1 Jul 2001
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Research ArticleCELLULAR AND MOLECULAR

Cytosolic Phospholipase A2 Activation by the p38 Kinase Inhibitor SB203580 in Rabbit Aortic Smooth Muscle Cells

S. Fatima, Z. Khandekar, J.-H. Parmentier and Kufait U. Malik
Journal of Pharmacology and Experimental Therapeutics July 1, 2001, 298 (1) 331-338;

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Research ArticleCELLULAR AND MOLECULAR

Cytosolic Phospholipase A2 Activation by the p38 Kinase Inhibitor SB203580 in Rabbit Aortic Smooth Muscle Cells

S. Fatima, Z. Khandekar, J.-H. Parmentier and Kufait U. Malik
Journal of Pharmacology and Experimental Therapeutics July 1, 2001, 298 (1) 331-338;
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