Carbon Monoxide Generated by Heme Oxygenase 1 Suppresses Endothelial Cell Apoptosis

DOI PDF 被引用文献36件
  • Sophie Brouard
    aImmunobiology Research Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215
  • Leo E. Otterbein
    bDepartment of Internal Medicine, Pulmonary and Critical Care Section, Yale University, School of Medicine, New Haven, Connecticut 06520
  • Josef Anrather
    cDepartment of Neurobiology, Weill Medical College of Cornell University, New York, New York 10021
  • Edda Tobiasch
    aImmunobiology Research Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215
  • Fritz H. Bach
    aImmunobiology Research Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215
  • Augustine M.K. Choi
    bDepartment of Internal Medicine, Pulmonary and Critical Care Section, Yale University, School of Medicine, New Haven, Connecticut 06520
  • Miguel P. Soares
    aImmunobiology Research Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215

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<jats:p>Heme oxygenase 1 (HO-1) inhibits apoptosis by regulating cellular prooxidant iron. We now show that there is an additional mechanism by which HO-1 inhibits apoptosis, namely by generating the gaseous molecule carbon monoxide (CO). Overexpression of HO-1, or induction of HO-1 expression by heme, protects endothelial cells (ECs) from apoptosis. When HO-1 enzymatic activity is blocked by tin protoporphyrin (SnPPIX) or the action of CO is inhibited by hemoglobin (Hb), HO-1 no longer prevents EC apoptosis while these reagents do not affect the antiapoptotic action of bcl-2. Exposure of ECs to exogenous CO, under inhibition of HO-1 activity by SnPPIX, substitutes HO-1 in preventing EC apoptosis. The mechanism of action of HO-1/CO is dependent on the activation of the p38 mitogen-activated protein kinase (MAPK) signaling transduction pathway. Expression of HO-1 or exposure of ECs to exogenous CO enhanced p38 MAPK activation by TNF-α. Specific inhibition of p38 MAPK activation by the pyridinyl imidazol SB203580 or through overexpression of a p38 MAPK dominant negative mutant abrogated the antiapoptotic effect of HO-1. Taken together, these data demonstrate that the antiapoptotic effect of HO-1 in ECs is mediated by CO and more specifically via the activation of p38 MAPK by CO.</jats:p>

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