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Heme oxygenase‐1‐derived carbon monoxide protects hearts from transplant‐associated ischemia reperfusion injury
Author(s) -
Akamatsu Yorihiro,
Haga Manabu,
Tyagi Shivraj,
Yamashita Kenichiro,
GraçaSouza Aurelio Vicente,
Ollinger Robert,
Czismadia Eva,
May G. Aaron,
Ifedigbo Emeka,
Otterbein Leo E.,
Bach Fritz H.,
Soares Miguel P.
Publication year - 2004
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.03-0921fje
Subject(s) - heme oxygenase , transplantation , biliverdin , reperfusion injury , heme , zinc protoporphyrin , pharmacology , medicine , ischemia , fibrin , carbon monoxide , chemistry , immunology , biochemistry , enzyme , catalysis
Heme oxygenase‐1 (HO‐1) degrades heme into iron, biliverdin, and carbon monoxide (CO). HO‐ 1 expression can be used therapeutically to ameliorate undesirable consequences of ischemia reperfusion injury (IRI), but the mechanism by which this occurs, remains to be established. Rat hearts, exposed to a prolonged period (24 h) of cold (4°C) ischemia, failed to function upon transplantation into syngeneic recipients. Induction of HO‐1 expression by administration of cobalt protoporphyrin IX (CoPPIX) to the graft donor restored graft function. Inhibition of HO‐1 enzymatic activity, by administration of zinc protoporphyrin (ZnPPIX) at the time of transplantation, reversed the protective effect of HO‐1. Exposure of the graft donor as well as the graft (during ischemia) to exogenous CO mimicked the protective effect of HO‐1. This was associated with a significant reduction in the number of cells undergoing apoptosis in the graft with no apparent decrease of intravascular fibrin polymerization, platelet aggregation, or P‐ selectin expression. In conclusion, HO‐1‐derived CO prevents IRI associated with cardiac transplantation based on its antiapoptotic action. The observation that exposure of the donor and the graft to CO is sufficient to afford this protective effect should have important clinical implications in terms of preventing IRI associated with heart transplantation in humans.