Carbon monoxide generated by heme oxygenase-1 suppresses the rejection of mouse-to-rat cardiac transplants

Mouse-to-rat cardiac transplants survive long term after transient compleme nt depletion by cobra venom factor and T cell immunosuppression by cyclospo rin A. Expression of heme oxygenase-1 (HO-1) by the graft vasculature is cr itical to achieve graft survival. In the present study, we asked whether th is protective effect was attributable to the generation of one of the catab olic products of HO-1, carbon monoxide (CO), Our present data suggests that this is the case, Under the same immunosuppressive regimen that allows mou se-to-rat cardiac transplants to survive long term (i,e,, cobra venom facto r plus cyclosporin A), inhibition of HO-1 activity by tin protoporphyrin, c aused graft rejection in 3-7 days. Rejection was associated with widespread platelet sequestration, thrombosis of coronary arterioles, myocardial infa rction, and apoptosis of endothelial cells as well as cardiac myocytes, Und er inhibition of HO-1 activity by tin protoporphyrin, exogenous CO suppress ed graft rejection and restored longterm graft survival. This effect of CO was associated with inhibition of platelet aggregation, thrombosis, myocard ial infarction, and apoptosis, We also found that expression of HO-1 by end othelial cells in vitro inhibits platelet aggregation and protects endothel ial cells from apoptosis, Both these actions of HO-1 are mediated through t he generation of CO. These data suggests that HO-1 suppresses the rejection of mouse-to-rat cardiac transplants through a mechanism that involves the generation of CO, Presumably CO suppresses graft rejection by inhibiting pl atelet aggregation that facilitates vascular thrombosis and myocardial infa rction, Additional mechanisms hy which CO overcomes graft rejection may inv olve its ability to suppress endothelial cell apoptosis.