HEME OXYGENASE-1 OVEREXPRESSION PROTECTS RAT HEARTS FROM COLD ISCHEMIA/REPERFUSION INJURY VIA AN ANTIAPOPTOTIC PATHWAY1

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Abstract
Background. Ischemia/reperfusion (I/R) injury is one of the most important causes of the early graft loss. We have shown that overexpression of heme oxygenase-1 (HO-1), an inducible heat shock protein 32, protects rat livers against I/R injury. We report on the cytoprotective effects of HO-1 in a rat cardiac I/R injury model, using cobalt protoporphyrin (CoPP) as HO-1 inducer and zinc protoporphyrin (ZnPP) as HO-1 inhibitor. Methods. Three groups of Lewis rats were studied: group 1 control donors received phosphate-buffered saline 48 hr before the harvest; group 2 donors were pretreated with CoPP at −48 hr; and in group 3, donors received CoPP at −48 hr and ZnPP was given to recipients at reperfusion. Hearts were harvested, stored in University of Wisconsin solution (4°C) for 24 hr, and then transplanted to syngeneic (Lewis) rats. Results. Sixty percent of control grafts ceased their function in <15 min. In contrast, 80% of CoPP-pretreated grafts survived 14 days. All grafts stopped functioning within 24 hr after CoPP + ZnPP therapy. Cardiac HO-1 enzymatic activity and protein expression correlated with beneficial effects of CoPP and deleterious effects of adjunctive ZnPP treatment. Markedly less apoptotic (TUNEL+) myocyte/endothelial cells could be detected in CoPP cardiac grafts, as compared with controls. The expression of antiapoptotic (Bcl-2/Bag-1) proteins was up-regulated in the CoPP group. Conclusion. HO-1 overexpression provides potent protection against cold I/R injury in a stringent rat cardiac model. This effect depends, at least in part, on HO-1-mediated up-regulation of a host antiapoptotic mechanism, especially in the early postreperfusion period.