TY - JOUR T1 - Carbon monoxide releasing molecule-2 inhibits pancreatic stellate cell proliferation by activating p38 MAPK/ HO-1 signaling JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.109.059519 SP - mol.109.059519 AU - Christian I Schwer AU - Manuel Mutschler AU - Ulrich Goebel AU - Patrick Stoll AU - Matjaz Humar AU - Alexander Hoetzel AU - Rene Schmidt Y1 - 2010/01/06 UR - http://molpharm.aspetjournals.org/content/early/2010/01/06/mol.109.059519.abstract N2 - 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 anti-proliferative effects on PSCs, but no information is available on the possible role of carbon monoxide (CO), a catalytic by-product 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 non-toxic 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 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.The American Society for Pharmacology and Experimental Therapeutics ER -