title: Carbon monoxide releasing molecule-2 inhibits pancreatic stellate cell proliferation by activating p38 mitogen-activated protein kinase/heme oxygenase-1 signaling.
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 G(0)/G(1) 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 p21(Waf1/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 p21(Waf1/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 p21(Waf1/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 p21(Waf1/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.
authors.affiliation: Department of Anesthesiology, University Medical Center, Hugstetter Strasse 55, D-79106 Freiburg, Germany.
authors.forename: Christian I
authors.initials: CI
authors.lastname: Schwer
authors.forename: Manuel
authors.initials: M
authors.lastname: Mutschler
authors.forename: Patrick
authors.initials: P
authors.lastname: Stoll
authors.forename: Ulrich
authors.initials: U
authors.lastname: Goebel
authors.forename: Matjaz
authors.initials: M
authors.lastname: Humar
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoetzel
authors.forename: Rene
authors.initials: R
authors.lastname: Schmidt
mesh_terms: D000818:Animals; D002248:Carbon Monoxide / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000032:analysis; D051547:Heme Oxygenase-1 / Q000502:physiology*; D020935:MAP Kinase Signaling System; D008297:Male; D009942:Organometallic Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D010179:Pancreas / Q000166:cytology / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology*
chemical_list: C493958:Cdkn1a protein, rat; D050759:Cyclin-Dependent Kinase Inhibitor p21; D009942:Organometallic Compounds; C447082:tricarbonyldichlororuthenium (II) dimer; D002248:Carbon Monoxide; D051547:Heme Oxygenase-1; D048051:p38 Mitogen-Activated Protein Kinases