Cytosolic phospholipase A2 activation by the p38 kinase inhibitor SB203580 in rabbit aortic smooth muscle cells

S. Fatima, Z. Khandekar, J. H. Parmentier, Kafait Malik

Research output: Contribution to journalArticle

29 Citations (Scopus)

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 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.

Original languageEnglish (US)
Pages (from-to)331-338
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume298
Issue number1
StatePublished - Jul 5 2001

Fingerprint

Cytosolic Phospholipases A2
Smooth Muscle Myocytes
Phosphotransferases
Rabbits
Nuclear Envelope
Phosphorylation
Mitogen-Activated Protein Kinase 3
Calmodulin
Arachidonic Acid
Anisomycin
SB 203580
Mitogen-Activated Protein Kinase 1
p38 Mitogen-Activated Protein Kinases
Nifedipine
Vascular Smooth Muscle
Aorta
Cytoplasm
Calcium

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

Cite this

Cytosolic phospholipase A2 activation by the p38 kinase inhibitor SB203580 in rabbit aortic smooth muscle cells. / Fatima, S.; Khandekar, Z.; Parmentier, J. H.; Malik, Kafait.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 298, No. 1, 05.07.2001, p. 331-338.

Research output: Contribution to journalArticle

@article{bf1437838c4b4f3285d58b541701fe56,
title = "Cytosolic phospholipase A2 activation by the p38 kinase inhibitor SB203580 in rabbit aortic smooth muscle cells",
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 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.",
author = "S. Fatima and Z. Khandekar and Parmentier, {J. H.} and Kafait Malik",
year = "2001",
month = "7",
day = "5",
language = "English (US)",
volume = "298",
pages = "331--338",
journal = "Journal of Pharmacology and Experimental Therapeutics",
issn = "0022-3565",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "1",

}

TY - JOUR

T1 - Cytosolic phospholipase A2 activation by the p38 kinase inhibitor SB203580 in rabbit aortic smooth muscle cells

AU - Fatima, S.

AU - Khandekar, Z.

AU - Parmentier, J. H.

AU - Malik, Kafait

PY - 2001/7/5

Y1 - 2001/7/5

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 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=0034743620&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0034743620&partnerID=8YFLogxK

M3 - Article

C2 - 11408559

AN - SCOPUS:0034743620

VL - 298

SP - 331

EP - 338

JO - Journal of Pharmacology and Experimental Therapeutics

JF - Journal of Pharmacology and Experimental Therapeutics

SN - 0022-3565

IS - 1

ER -