title: Riboflavin-mediated reduction of oxidant injury, rejection, and vasculopathy after cardiac allotransplantation.
abstract: BACKGROUND
  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).
  
  
  METHODS
  A murine heterotopic cardiac transplantation model was used to test whether riboflavin improves I/R injury and acute/chronic rejection.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Internal Medicine, University of Michigan Cardiovascular Center, Ann Arbor, MI 48109, USA.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Iwanaga
authors.forename: Tomomi
authors.initials: T
authors.lastname: Hasegawa
authors.forename: Donald E
authors.initials: DE
authors.lastname: Hultquist
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Harada
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Yoshikawa
authors.forename: Sunitha
authors.initials: S
authors.lastname: Yanamadala
authors.forename: Hui
authors.initials: H
authors.lastname: Liao
authors.forename: Scott H
authors.initials: SH
authors.lastname: Visovatti
authors.forename: David J
authors.initials: DJ
authors.lastname: Pinsky
mesh_terms: D000818:Animals; D003327:Coronary Disease / Q000503:physiopathology / Q000517:prevention & control; D004195:Disease Models, Animal; D018450:Disease Progression; D006084:Graft Rejection / Q000503:physiopathology / Q000517:prevention & control*; D016027:Heart Transplantation / Q000009:adverse effects* / Q000502:physiology; D015227:Lipid Peroxidation / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D016877:Oxidants / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D015427:Reperfusion Injury / Q000503:physiopathology / Q000517:prevention & control*; D012256:Riboflavin / Q000627:therapeutic use*; D014184:Transplantation, Homologous; D014803:Vitamin B Complex / Q000627:therapeutic use*
chemical_list: D016877:Oxidants; D014803:Vitamin B Complex; D012256:Riboflavin