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HO\u2010 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\u00b0C) ischemia, failed to function upon transplantation into syngeneic recipients. Induction of HO\u20101 expression by administration of cobalt protoporphyrin IX (CoPPIX) to the graft donor restored graft function. Inhibition of HO\u20101 enzymatic activity, by administration of zinc protoporphyrin (ZnPPIX) at the time of transplantation, reversed the protective effect of HO\u20101. Exposure of the graft donor as well as the graft (during ischemia) to exogenous CO mimicked the protective effect of HO\u20101. 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\u2010 selectin expression. In conclusion, HO\u20101\u2010derived CO prevents IRI associated with cardiac transplantation based on its antiapoptotic action. 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