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

Abstract

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.

Suppression of nitrosative and oxidative stress to reduce cardiac allograft vasculopathy

“…These findings indicate the possibility that an antioxidant given during the peri-implantation period can modulate both cellular and humoral immune responses and play an important role in allograft tolerance induction. In our previous study (15), there was no significant effect of riboflavin on the development of alloantibodies 4 -8 wk after transplantation. We concluded there that humoral sensitization is not likely to be the dominant reason for the clear-cut suppression by riboflavin of CAV development.…”

“…Riboflavin is a particularly intriguing antioxidant, as it is reduced to dihydroriboflavin by flavin reductase, a cytoplasmic NADPH-dependent reductase, which not only rapidly terminally quenches ROS as they are formed, but is regenerated cyclically as reducing equivalents are generated. Although there has been some previous work suggesting beneficial effects of riboflavin in various conditions of ischemia and reperfusion injury, including transplantation (14,15,18), the physiological protective mechanisms that are bolstered by riboflavin have been the subject of conjecture.…”

“…Completely allomismatched murine heterotopic cardiac transplantation was performed using two rejection models, acute and chronic, as described previously (12,15).…”

“…Prior work has shown that an antioxidant such as riboflavin could protect cardiac allografts, but the mechanisms underlying this protection have not been fully defined (15). Riboflavin, as a naturally occurring antioxidant, which can repeatedly cycle through biological redox cycles to continually eliminate oxidative species (14,18), could be an outstanding agent to test the effect of oxidative stress, as well as its mitigation in the setting of cardiac transplantation.…”

Riboflavin Inhibits IL-6 Expression and p38 Activation in Islet Cells

“…can upregulate other mediators of cell death such as NF-κB and JNK, which have also been shown to affect islet Flavoproteins play a role in several red-ox reactions in the cells (13) and can modulate both innate and acquired cell viability and function (11,32). In addition, inhibition of p38 has been shown to improve early islet revascuimmune responses (47) as well as reduce cellular injury caused by oxidative stress (21,28,43). Riboflavin has been larization after transplantation (22), to increase viability of cryopreserved islets (31), and to reduce the producshown to significantly improve survival rate in a murine model of lipopolysaccharide-induced shock (25,45,46), tion of inflammatory cytokines by human islets (29).…”