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Molecular Pharmacology

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Research ArticleArticle

Carbon Monoxide Releasing Molecule-2 Inhibits Pancreatic Stellate Cell Proliferation by Activating p38 Mitogen-Activated Protein Kinase/Heme Oxygenase-1 Signaling

Christian I. Schwer, Manuel Mutschler, Patrick Stoll, Ulrich Goebel, Matjaz Humar, Alexander Hoetzel and Rene Schmidt
Molecular Pharmacology April 2010, 77 (4) 660-669; DOI: https://doi.org/10.1124/mol.109.059519
Christian I. Schwer
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Manuel Mutschler
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Patrick Stoll
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Ulrich Goebel
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Matjaz Humar
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Alexander Hoetzel
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Rene Schmidt
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Abstract

Proliferation of pancreatic stellate cells (PSCs) plays a cardinal role during fibrosis development. Therefore, the suppression of PSC growth represents a therapeutic option for the treatment of pancreatic fibrosis. It has been shown that up-regulation of the enzyme heme oxygenase-1 (HO-1) could exert antiproliferative effects on PSCs, but no information is available on the possible role of carbon monoxide (CO), a catalytic byproduct of the HO metabolism, in this process. In the present study, we have examined the effect of CO releasing molecule-2 (CORM-2) liberated CO on PSC proliferation and have elucidated the mechanisms involved. Using primary rat PSCs, we found that CORM-2 inhibited PSC proliferation at nontoxic concentrations by arresting cells at the G0/G1 phase of the cell cycle. This effect was associated with activation of p38 mitogen-activated protein kinase (MAPK) signaling, induction of HO-1 protein, and up-regulation of the cell cycle inhibitor p21Waf1/Cip1. The p38 MAPK inhibitor 4-(4-flurophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)imidazole (SB203580) abolished the inhibitory effect of CORM-2 on PSC proliferation and prevented both CORM-2-induced HO-1 and p21Waf1/Cip1 up-regulation. Treatment with tin protoporphyrin IX, an HO inhibitor, or transfection of HO-1 small interfering RNA abolished the inductive effect of CORM-2 on p21Waf1/Cip1 and reversed the suppressive effect of CORM-2 on PSC growth. The ability of CORM-2 to induce cell cycle arrest was abrogated in p21Waf1/Cip1-silenced cells. Taken together, our results suggest that CORM-2 inhibits PSC proliferation by activation of the p38/HO-1 pathway. These findings may indicate a therapeutic potential of CO carriers in the treatment of pancreatic fibrosis.

Footnotes

    fn-1
  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.109.059519.

  • fn-2
  • ABBREVIATIONS:

    PSC
    pancreatic stellate cell
    ANOVA
    analysis of variance
    BrdU
    5-bromo-2′-deoxyuridine
    Cdk
    cyclin-dependent kinase
    CORM
    carbon monoxide-releasing molecule
    CORM-2
    tricarbonyldichlororuthenium(II) dimer
    ERK
    extracellular signal-regulated kinase
    FCS
    fetal calf serum
    GAPDH
    glyceraldehyde 3-phosphate dehydrogenase
    HO-1
    heme oxygenase-1
    IMDM
    Iscove's modified Dulbecco's medium
    JNK
    c-Jun NH2-terminal kinase
    MAPK
    mitogen-activated protein kinase
    SB203580
    4-(4-flurophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl) imidazole
    siRNA
    small interfering RNA
    SnPP
    tin protoporphyrin IX
    DMSO
    dimethyl sulfoxide
    LDH
    lactate dehydrogenase
    MKK
    mitogen-activated protein kinase kinase
    MAPKAPK
    mitogen-activated protein kinase-activated protein kinase
    SB202474
    4-ethyl-2-(p-methoxyphenyl)-5-(4′-pyridyl)-1H-imidazole.

    • Received July 17, 2009.
    • Accepted January 6, 2010.
  • Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 77 (4)
Molecular Pharmacology
Vol. 77, Issue 4
1 Apr 2010
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Research ArticleArticle

Carbon Monoxide Releasing Molecule-2 Inhibits Pancreatic Stellate Cell Proliferation by Activating p38 Mitogen-Activated Protein Kinase/Heme Oxygenase-1 Signaling

Christian I. Schwer, Manuel Mutschler, Patrick Stoll, Ulrich Goebel, Matjaz Humar, Alexander Hoetzel and Rene Schmidt
Molecular Pharmacology April 1, 2010, 77 (4) 660-669; DOI: https://doi.org/10.1124/mol.109.059519

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Research ArticleArticle

Carbon Monoxide Releasing Molecule-2 Inhibits Pancreatic Stellate Cell Proliferation by Activating p38 Mitogen-Activated Protein Kinase/Heme Oxygenase-1 Signaling

Christian I. Schwer, Manuel Mutschler, Patrick Stoll, Ulrich Goebel, Matjaz Humar, Alexander Hoetzel and Rene Schmidt
Molecular Pharmacology April 1, 2010, 77 (4) 660-669; DOI: https://doi.org/10.1124/mol.109.059519
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