Heme oxygenase-1 improves the survival of discordant cardiac xenograft through its anti-inflammatory and anti-apoptotic effects.

HO-1 is a rate-limiting enzyme in hemoglobin metabolism, and exerts anti-inflammatory as well as anti-apoptotic effects. Previous studies have shown that expression of HO-1 can prolong the survival of concordant transplanted organs. However, little is known about the precise effect and mechanism of HO-1 in discordant xenotransplantation. In this study, we investigated the role of HO-1 in discordant cardiac xenotransplantation. First, HUVECs were used to assess the effect of HO-1 on TNF-alpha-induced apoptosis. Results showed that TNF-alpha induced apoptosis of HUVECs in a dose-dependent manner. Moreover, induction of HO-1 by hemin suppressed TNF-alpha-induced apoptosis. However, the anti-apoptotic action of HO-1 was reversed by SnPP. The up-regulation of HO-1 by hemin treatment significantly prolonged the survival time of discordant cardiac xenograft, greatly reduced the swelling and apoptosis of myocardial cells, interstitial edema, lymphocyte infiltration, and thrombus formation in small vessels. Furthermore, HO-1 overexpression significantly attenuated the serum level of xenoantibody IgM, tissue deposition of IgM and complement 3 (C(3)) in endangium. Finally, HO-1 mitigated CD40L transcription in the xenograft and recipient spleen. These results indicate that the up-regulation of HO-1 can improve the survival of discordant cardiac xenograft by inhibiting apoptosis and alleviating inflammation and thrombosis.