Expression of heme oxygenase-1 can determine cardiac xenograft survival.
The rejection of concordant xenografts, such as mouse-to-rat cardiac xenografts, is very similar to the delayed rejection of porcine-to-primate discordant xenografts. In concordant models, this type of rejection is prevented by brief complement inhibition by cobra venom factor (CVF) and sustained T-cell immunosuppression by cyclosporin A (CyA). Mouse hearts that survive indefinitely in rats treated with CVF plus CyA express the anti-inflammatory gene heme oxygenase-1 (HO-1) in their endothelial cells and smooth muscle cells. The anti-inflammatory properties of HO-1 are thought to rely on the ability of this enzyme to degrade heme and generate bilirubin, free iron and carbon monoxide. Bilirubin is a potent anti-oxidant, free iron upregulates the transcription of the cytoprotective gene, ferritin, and carbon monoxide is thought to be essential in regulating vascular relaxation in a manner similar to nitric oxide. We show here that the expression of the HO-1 gene is functionally associated with xenograft survival, and that rapid expression of HO-1 in cardiac xenografts can be essential to ensure long-term xenograft survival.
Soares
M P
MP
Immunobiology Research Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA. msoares@bidmc.harvard.edu
Lin
Y
Y
Anrather
J
J
Csizmadia
E
E
Takigami
K
K
Sato
K
K
Grey
S T
ST
Colvin
R B
RB
Choi
A M
AM
Poss
K D
KD
Bach
F H
FH
D000818:Animals; D017209:Apoptosis; D003169:Complement Inactivator Proteins / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004546:Elapid Venoms / Q000494:pharmacology; D006084:Graft Rejection / Q000276:immunology; D006085:Graft Survival / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology*; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000502:physiology*; D051547:Heme Oxygenase-1; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008565:Membrane Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000166:cytology; D051381:Rats; D014183:Transplantation, Heterologous / Q000276:immunology*
D003169:Complement Inactivator Proteins; D004268:DNA-Binding Proteins; D004546:Elapid Venoms; D007166:Immunosuppressive Agents; D008565:Membrane Proteins; C499308:Rag2 protein, mouse; C064655:V(D)J recombination activating protein 2; C016310:cobra venom factor; D016572:Cyclosporine; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse