TY - JOUR
T1 - Carbon monoxide donors or heme oxygenase-1 (HO-1) overexpression blocks interleukin-18-mediated NF-κB-PTEN-dependent human cardiac endothelial cell death
AU - Zabalgoitia, Miguel
AU - Colston, James T.
AU - Reddy, Seenu V.
AU - Holt, Jeffrey W.
AU - Regan, Raymond F.
AU - Stec, David E.
AU - Rimoldi, John M.
AU - Valente, Anthony J.
AU - Chandrasekar, Bysani
PY - 2008/2/1
Y1 - 2008/2/1
N2 - 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.
AB - 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.
KW - Bilirubin
KW - Biliverdin
KW - Carbon monoxide
KW - Cell death
KW - Heme oxygenase
KW - Interleukin-18
KW - NF-κB
KW - PTEN
UR - http://www.scopus.com/inward/record.url?scp=38149135752&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=38149135752&partnerID=8YFLogxK
U2 - 10.1016/j.freeradbiomed.2007.08.012
DO - 10.1016/j.freeradbiomed.2007.08.012
M3 - Article
C2 - 18215737
AN - SCOPUS:38149135752
SN - 0891-5849
VL - 44
SP - 284
EP - 298
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
IS - 3
ER -