Heme oxygenase-1 overexpression protects rat hearts from cold ischemia/reperfusion injury via an antiapoptotic pathway.
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 degrees 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.


CONCLUSIONS
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.
Katori
Masamichi
M
Division of Liver and Pancreas Transplantation, Dumot-UCLA Transplant Center, Los Angeles, California 90095, USA.
Buelow
Roland
R
Ke
Bibo
B
Ma
Jeff
J
Coito
Ana J
AJ
Iyer
Suhasini
S
Southard
Daniel
D
Busuttil
Ronald W
RW
Kupiec-Weglinski
Jerzy W
JW
D000818:Animals; D017209:Apoptosis; D016027:Heart Transplantation; D006419:Heme Oxygenase (Decyclizing) / Q000502:physiology*; D051547:Heme Oxygenase-1; D018398:Homeodomain Proteins / Q000032:analysis; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D019001:Nitric Oxide Synthase / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D011524:Protoporphyrins / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew
D018398:Homeodomain Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011524:Protoporphyrins; C064658:RAG-1 protein; C017803:zinc protoporphyrin; C007095:cobaltiprotoporphyrin; D019001:Nitric Oxide Synthase; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1