Carbon monoxide generated by heme oxygenase 1 suppresses endothelial cell apoptosis

Sophie Brouard, Leo E. Otterbein, Josef Anrather, Edda Tobiasch, Fritz H. Bach, Augustine M.K. Choi, Miguel P. Soares

Research output: Contribution to journalArticle

826 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1015-1025
Number of pages11
JournalJournal of Experimental Medicine
Volume192
Issue number7
DOIs
StatePublished - Oct 2 2000

Keywords

  • Apoptosis
  • Carbon monoxide
  • Endothelial cells
  • Heme oxygenase 1
  • p38 mitogen-activated protein kinase

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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