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Research ArticleCARDIOVASCULAR

Sustained Activation of p38 Mitogen-Activated Protein Kinase Contributes to the Vascular Response to Injury

Haisong Ju, Sandhya Nerurkar, Charles F. Sauermelch, Alan R. Olzinski, Rosanna Mirabile, Dawn Zimmerman, John C. Lee, Jerry Adams, Joseph Sisko, Marinella Berova and Robert N. Willette
Journal of Pharmacology and Experimental Therapeutics April 2002, 301 (1) 15-20; DOI: https://doi.org/10.1124/jpet.301.1.15
Haisong Ju
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Sandhya Nerurkar
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Charles F. Sauermelch
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Alan R. Olzinski
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Rosanna Mirabile
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Dawn Zimmerman
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John C. Lee
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Jerry Adams
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Joseph Sisko
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Marinella Berova
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Robert N. Willette
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Abstract

The vascular response to mechanical injury involves inflammatory and fibroproliferative processes that result in the formation of neointima and vascular remodeling. The complex cellular interactions initiated by vascular injury are coordinated and modulated by the elaboration of cytokines and growth factors. The production and transduction of many of these mediators require phosphorylation of p38 mitogen-activated protein kinase (MAPK). In the present investigation, we examined the pattern and localization of p38 MAPK activation following balloon vascular injury. The effects of long-term and selective inhibition of p38 MAPK with SB 239063 (trans-1-(4-hydroxycyclohexyl)-4-(4-fluorophenyl)-5-[2-methoxy)pyrimidin-4-yl]imidazole) were also investigated in a model of vascular injury. Western blotting and immunohistochemical staining demonstrated that phospho-p38 MAPK was increased following balloon injury of the rabbit iliofemoral artery. The p38 MAPK activation was noted as early as 15 min after balloon injury and remained elevated for at least 28 days. Phospho-p38 MAPK immunoreactivity (IR) was localized primarily in regions of dedifferentiated, smooth muscle α-actin-positive cells in all lamina of the vessel wall. Phospho-p38 MAPK IR was not correlated with the localization of macrophage or proliferating cells (proliferating cell nuclear antigen; PCNA +). Long-term treatment (4 weeks) with SB 239063 (50 mg/kg/day, p.o.) reduced the vascular response to injury in the hypercholesterolemic rabbit. SB 239063 had no effect on platelet-derived growth factor (PDGF)-stimulated migration or proliferation of rabbit vascular smooth muscle cells (VSMCs) in culture. However, SB 239063 produced a concentration-dependent inhibition of transforming growth factor (TGF)-β-stimulated fibronectin production in VSMCs. In conclusion, sustained activation of p38 MAPK plays an important role in the vascular response to injury and inhibition of p38 MAPK may represent a novel therapeutic approach to limit this response.

Footnotes

  • Abbreviations:
    VSMCs
    vascular smooth muscle cells
    MAPK
    mitogen-activated protein kinase
    IR
    immunoreactivity
    IL
    interleukin
    TNF
    tumor necrosis factor
    PCNA
    proliferating cell nuclear antigen
    PDGF
    platelet-derived growth factor
    FBS
    fetal bovine serum
    TGF
    transforming growth factor
    SB 239063
    trans-1-(4-hydroxycyclohexyl)-4-(4-fluorophenyl)-5-[(2-methoxy)pyrimidin-4-yl]imidazole
    FR167653
    1[7-(4-fluorophenyl)-1,2,3,4-tetrahydro-8-(4-pyridyl)pyrazolo[5,1-c][1,2,4]triazin-2-yl]-2-phenylethanedione sulfate monohydrate
    RAM-11
    rabbit anti-macrophage
    • Received September 14, 2001.
    • Accepted December 17, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 301 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 301, Issue 1
1 Apr 2002
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Research ArticleCARDIOVASCULAR

Sustained Activation of p38 Mitogen-Activated Protein Kinase Contributes to the Vascular Response to Injury

Haisong Ju, Sandhya Nerurkar, Charles F. Sauermelch, Alan R. Olzinski, Rosanna Mirabile, Dawn Zimmerman, John C. Lee, Jerry Adams, Joseph Sisko, Marinella Berova and Robert N. Willette
Journal of Pharmacology and Experimental Therapeutics April 1, 2002, 301 (1) 15-20; DOI: https://doi.org/10.1124/jpet.301.1.15

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Research ArticleCARDIOVASCULAR

Sustained Activation of p38 Mitogen-Activated Protein Kinase Contributes to the Vascular Response to Injury

Haisong Ju, Sandhya Nerurkar, Charles F. Sauermelch, Alan R. Olzinski, Rosanna Mirabile, Dawn Zimmerman, John C. Lee, Jerry Adams, Joseph Sisko, Marinella Berova and Robert N. Willette
Journal of Pharmacology and Experimental Therapeutics April 1, 2002, 301 (1) 15-20; DOI: https://doi.org/10.1124/jpet.301.1.15
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