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(1,2-6). 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. 7-10). Mouse hearts that survive indefinitely in rats treated with CVF plus CyA express the anti-inflammatory gene heme oxygenase-l (HO-1) in their endothelial cells and smooth muscle cells(9,11-14). 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 monoxide(15) Bilirubin is a potent anti-oxidant(13), free iron upregulates the transcription of the cytoprotective gene, ferritin(16), and carbon monoxide is thought to be essential in regulating vascular relaxation in a manner similar to nitric oxide(15). 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.