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Expression of heme oxygenase-1 can determine cardiac xenograft survival

Abstract

The rejection of concordant xenografts, such as mouse-to-rat cardiac xenografts, is very similar to the delayed rejection of porcine-to-primate discordant xenografts1,2,3,4,5,6. 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) (refs. 7,8,9,10 ). 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 cells9,11,12,13,14. 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 monoxide15. Bilirubin is a potent anti-oxidant13, free iron upregulates the transcription of the cytoprotective gene, ferritin16, and carbon monoxide is thought to be essential in regulating vascular relaxation in a manner similar to nitric oxide15. 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.

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Figure 1: Immunopathology of xenograft rejection and survival.
Figure 2: Expression HO-1 in mouse cardiac xenografts.
Figure 3: Immunopathology of xenograft rejection in HO-1–/– hearts.
Figure 4: a, In situ detection of apoptosis by TUNEL analysis.

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Acknowledgements

We thank S. Sevillano for technical assistance with Immunohistological staining, C. Ferran and H. Winkler for comments, as well as members of our laboratory for discussion. This is paper 747 from our laboratories. This work was supported by a grant from Novartis Pharma, Basel, Switzerland. F.H.B. is the Lewis Thomas Professor at the Harvard Medical School and is a paid consultant for Novartis Pharma.

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Correspondence to M.P. Soares.

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Soares, M., Lin, Y., Anrather, J. et al. Expression of heme oxygenase-1 can determine cardiac xenograft survival . Nat Med 4, 1073–1077 (1998). https://doi.org/10.1038/2063

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