Riboflavin-Mediated Reduction of Oxidant Injury, Rejection, and Vasculopathy after Cardiac Allotransplantation

Abstract

Riboflavin is a well-known nutritional supplement that has been shown to exhibit antioxidant properties and protect tissue from oxidative damage. We hypothesized that riboflavin given during cardiac ischemia-reperfusion (I/R) might reduce subsequent acute rejection, after allotransplantation, and coronary allograft vasculopathy (CAV). A murine heterotopic cardiac transplantation model was used to test whether riboflavin improves I/R injury and acute/chronic rejection. Riboflavin significantly reduced oxidant production and inflammatory mediator production induced by I/R injury, as evidenced by decreased levels of malondialdehyde, myeloperoxidase activity, and tumor necrosis factor alpha. Administration of riboflavin also improved graft survival and suppressed T-cell infiltration and donor-reactive alloantibody formation during the early period after allotransplantation. A murine long-term cardiac allograft model using immunosuppression (preoperative anti-murine CD4 and anti-CD8) was employed to investigate the effect of riboflavin against CAV at 60 days. Riboflavin-treated grafts exhibited a significant decrease in the severity of coronary artery luminal occlusion as compared with saline-treated grafts (17.4+/-1.8% vs. 43.5+/-5.6%, P=0.0012). However, there was no significant effect of riboflavin to reduce donor-reactive alloantibodies in this chronic model. These data indicate that riboflavin improves early I/R injury and reduces the development of CAV, most likely due to alloantigen-independent effects such as reduced early graft oxidant stress. Riboflavin administered in the setting of cardiac allograft transplantation appears to be a powerful means to reduce early graft lipid peroxidation, leukocytic infiltration, and cytokine production as well as to suppress the late development of cardiac allograft vasculopathy.