Carbon monoxide donors or heme oxygenase-1 (HO-1) overexpression blocks interleukin-18-mediated NF-κB-PTEN-dependent human cardiac endothelial cell death

Miguel Zabalgoitia, James T. Colston, Seenu V. Reddy, Jeffrey W. Holt, Raymond F. Regan, David E. Stec, John M. Rimoldi, Anthony J. Valente, Bysani Chandrasekar

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

Abstract

The objective of this study was to determine whether heme oxygenase-1 (HO-1) or heme metabolites exert cytoprotective effects on interleukin-18-mediated endothelial cell (EC) death. Treatment with interleukin (IL)-18 increased NF-κB activation and PTEN induction, suppressed Akt activation, and stimulated EC death. While ectopic expression of p65 enhanced PTEN transcription, adenoviral transduction of dnIκB-α, dnp65, or dnIKKβ was inhibitory. Furthermore, IL-18 suppressed HO-1 mRNA expression via enhanced mRNA degradation. Overexpression of HO-1, treatment with HO-1 inducer hemin, or the CO donor cobalt (III) protoporphyrin IX all reversed IL-18-mediated NF-κB activation, PTEN induction, Akt suppression, and EC death. Furthermore, hemin induced HO-1 expression, and HO-1 knockdown, HO-1 inhibition, or CO scavengers all reversed the prosurvival effects of hemin. In addition, the CO donors CORM-1 and CORM-3 and the heme metabolites biliverdin and bilirubin attenuated IL-18-induced EC death via a similar signaling pathway. IL-18 induced p38α MAPK activation, and suppressed p38β isoform expression. While p38α knockdown attenuated, p38β knockdown potentiated IL-18-mediated EC death. Hemin and HO-1 reversed IL-18-mediated p38α induction and restored p38β levels. These results demonstrate that IL-18 suppresses HO-1 expression and induces EC death. HO-1 overexpression, HO-1 induction, or treatment with heme metabolites all reverse IL-18-mediated p38α MAPK and NF-κB activation, PTEN induction, Akt suppression, and EC death. Thus, HO-1 inducers and CO donors may have the therapeutic potential to effectively block IL-18 signaling and reduce IL-18-dependent vascular injury and inflammation.

Original languageEnglish (US)
Pages (from-to)284-298
Number of pages15
JournalFree Radical Biology and Medicine
Volume44
Issue number3
DOIs
StatePublished - Feb 1 2008

Keywords

  • Bilirubin
  • Biliverdin
  • Carbon monoxide
  • Cell death
  • Heme oxygenase
  • Interleukin-18
  • NF-κB
  • PTEN

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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