Over-expression Of Growth Differentiation Factor 15(GDF-15) Preventing Cold Ischemia Reperfusion (I/R) Injury In Heart Transplantation Through Foxo3a Signaling

Heart disease is the leading cause of death.Patient with end stage of heart disease suffered a low living quality.Heart transplantation is a standard treatment for end stage of heart diseases.However,there are too many element can lead heart transplantation to failing.Ischemia reperfusion(I/R)injury,which inevitably occurs during heart transplantation,is a major factor leading to organ failure and graft rejection.In order to develop new therapies to prevent I/R injury,we used both a murine heart transplantation model with 24 hour cold I/R and in vitro cell culture system to determine whether growth differentiation factor 15(GDF15)is a protective factor in preventing I/R injury in heart transplantation and to dissect underlying mechanisms.We found that cold I/R caused severe damage on heart grafts including endocardium,epicardium and myocardium in wild type C57BL/6 mice,whereas grafts from GDF15 transgenic(Tg)mice showed less damage as demonstrated by less cell death,less neutrophils infiltration and preservation of normal heart structure.Over-expression of GDF15 reduced expression of phosphorylated Rel A p65,a pre-inflammation and pro-apoptotic gene,while it enhanced Foxo3 a phosphorylation in vitro and in vivo.Over-expression of GDF15 inhibited cell apoptosis and reduced neutrophil infiltration.However,immunological rejection also can cause graft death or disfunction.Dendritic cell(DC)is an antigen present cell which plays an important role in immunoreaction.Compared DC from WT group and GDF-15 TG group,we observed DC from GDF-15 TG mice was less mature and less functional.Overexpressed GDF-15 also influenced T cell by causing more apoptosis of T cell.In conclusion,this study,for the first time,demonstrates that GDF15 is a promising target for preventing cold I/R injury in heart transplantation and that its protective effect is mediated by the Foxo3 signaling and NFκB signaling.Result:1.GDF15 protects heart from I/R injury in heart transplantation2.GDF15 inhibits cell apoptosis and reduces expression of proinflammatory cytokine production in heart graft in vivo3.GDF15 protects cardiomyocytes from cell apoptosis/death induced by I/R in vitro4.GDF15 protects heart cells from I/R injury through the Foxo3 a signaling pathway5.GDF-15 can induce DC less mature and disfunctional.Conclusions:GDF-15 over-express during cold I/R injury.In comparison with GDF-15 transgenic mice and wild-type mice,we observed that GDF-15 was able to protect against cold ischemia-reperfusion injury in the heart,showing that the transgenic mice remain more normal myocardial structure,less inflammatory cell infiltration,less fibrosis;in vitro model H9C2 cells after transfecting GDF-15 gene apoptosis and death less.And this protective effect on ischemia-reperfusion is achieved by upregulating phosphorylated Foxo3 a and inhibiting the expression of phosphorylated Rel A p65.GDF-15 can suppress immunological rejection by preventing DC from mature and functional,inducing T cell apoptosis.