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Research ArticleCARDIOVASCULAR

Angiotensin II-Induced Migration of Vascular Smooth Muscle Cells Is Mediated by p38 Mitogen-Activated Protein Kinase-Activated c-Src through Spleen Tyrosine Kinase and Epidermal Growth Factor Receptor Transactivation

Benon E. Mugabe, Fariborz A. Yaghini, Chi Young Song, Cuneyt K. Buharalioglu, Christopher M. Waters and Kafait U. Malik
Journal of Pharmacology and Experimental Therapeutics January 2010, 332 (1) 116-124; DOI: https://doi.org/10.1124/jpet.109.157552
Benon E. Mugabe
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Fariborz A. Yaghini
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Chi Young Song
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Cuneyt K. Buharalioglu
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Christopher M. Waters
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Kafait U. Malik
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This article has a correction. Please see:

  • Correction to “Angiotensin II-Induced Migration of Vascular Smooth Muscle Cells Is Mediated by p38 Mitogen-Activated Protein Kinase-Activated c-Src through Spleen Tyrosine Kinase and Epidermal Growth Factor Receptor Transactivation” - November 01, 2010

Abstract

Angiotensin II (Ang II) stimulates protein synthesis by activating spleen tyrosine kinase (Syk) and DNA synthesis through epidermal growth factor receptor (EGFR) transactivation in vascular smooth muscle cells (VSMCs). This study was conducted to determine whether Syk mediates Ang II-induced migration of aortic VSMCs using a scratch wound approach. Treatment with Ang II (200 nM) for 24 h increased VSMC migration by 1.56 ± 0.14-fold. Ang II-induced VSMC migration and Syk phosphorylation as determined by Western blot analysis were minimized by the Syk inhibitor piceatannol (10 μM) and by transfecting VSMCs with dominant-negative but not wild-type Syk plasmid. Ang II-induced VSMC migration and Syk phosphorylation were attenuated by inhibitors of c-Src [4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2)], p38 mitogen-activated protein kinase (MAPK) [4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)1H-imidazole (SB202190)], and extracellular signal-regulated kinase (ERK) 1/2 [1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio) butadiene (U0126)]. SB202190 attenuated p38 MAPK and c-Src but not ERK1/2 phosphorylation, indicating that p38 MAPK acts upstream of c-Src and Syk. The c-Src inhibitor PP2 attenuated Syk and ERK1/2 phosphorylation, suggesting that c-Src acts upstream of Syk and ERK1/2. Ang II- and epidermal growth factor (EGF)-induced VSMC migration and EGFR phosphorylation were inhibited by the EGFR blocker 4-(3-chloroanilino)-6,7-dimethoxyquinazoline (AG1478) (2 μM). Neither the Syk inhibitor piceatannol nor the dominant-negative Syk mutant altered EGF-induced cell migration or Ang II- and EGF-induced EGFR phosphorylation. The c-Src inhibitor PP2, dominant negative mutant of Src or Src small interfering RNA did not alter EGF-induced VSMC migration and EGFR, ERK1/2, and p38 MAPK phosphorylation. The ERK1/2 inhibitor U0126 (10 μM) attenuated EGF-induced cell migration and ERK1/2 but not EGFR phosphorylation. These data suggest that Ang II stimulates VSMC migration via p38 MAPK-activated c-Src through Syk and via EGFR transactivation through ERK1/2 and partly through p38 MAPK.

Footnotes

  • This work was supported in part by the National Institutes of Health National Heart, Lung, and Blood Institute [Grants R01-079109 and HL094366] (to K.U.M. and C.M.W., respectively); and the National Institutes of Health National Heart, Lung, and Blood Institute [Grant 2T32-HL00764] (Training Grant to B.E.M.). C.K.B. was supported by the Scientific and Technical Research Council of Turkey (TUBITAK).

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    doi:10.1124/jpet.109.157552

  • ↵Embedded Image The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    Ang II
    angiotensin II
    VSMC
    vascular smooth muscle cell
    MAPK
    mitogen-activated protein kinase
    ERK
    extracellular signal-regulated kinase
    p38 MAPK
    p38 mitogen-activated protein kinase
    c-JNK
    c-Jun N-terminal kinase
    Pyk2
    proline-rich tyrosine kinase
    c-Src
    c-terminal nonreceptor tyrosine kinase
    EGF
    epidermal growth factor
    EGFR
    epidermal growth factor receptor
    Syk
    spleen tyrosine kinase
    AG1478
    (4-(3-chloroanilino)-6,7-dimethoxyquinazoline
    SB202190
    4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)1H-imidazole
    U0126
    1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene)
    piceatannol
    trans-3,3′-4,5′-tetrahydroxy-stilbene
    PP2
    4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine
    WT
    wild type
    DN
    dominant negative.

  • Received June 15, 2009.
  • Accepted September 29, 2009.
  • © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 332 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 332, Issue 1
1 Jan 2010
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Research ArticleCARDIOVASCULAR

Angiotensin II-Induced Migration of Vascular Smooth Muscle Cells Is Mediated by p38 Mitogen-Activated Protein Kinase-Activated c-Src through Spleen Tyrosine Kinase and Epidermal Growth Factor Receptor Transactivation

Benon E. Mugabe, Fariborz A. Yaghini, Chi Young Song, Cuneyt K. Buharalioglu, Christopher M. Waters and Kafait U. Malik
Journal of Pharmacology and Experimental Therapeutics January 1, 2010, 332 (1) 116-124; DOI: https://doi.org/10.1124/jpet.109.157552

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Research ArticleCARDIOVASCULAR

Angiotensin II-Induced Migration of Vascular Smooth Muscle Cells Is Mediated by p38 Mitogen-Activated Protein Kinase-Activated c-Src through Spleen Tyrosine Kinase and Epidermal Growth Factor Receptor Transactivation

Benon E. Mugabe, Fariborz A. Yaghini, Chi Young Song, Cuneyt K. Buharalioglu, Christopher M. Waters and Kafait U. Malik
Journal of Pharmacology and Experimental Therapeutics January 1, 2010, 332 (1) 116-124; DOI: https://doi.org/10.1124/jpet.109.157552
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