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Over-expression of growth differentiation factor 15 (GDF15) preventing cold ischemia reperfusion (I/R) injury in heart transplantation through Foxo3a signaling.
- Source :
-
Oncotarget [Oncotarget] 2017 May 30; Vol. 8 (22), pp. 36531-36544. - Publication Year :
- 2017
-
Abstract
- Ischemia reperfusion (I/R) injury which inevitably occurs during heart transplantation is the 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 an 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 further investigate underlying mechanisms of I/R injury. We found that cold I/R caused severe damage to the endocardium, epicardium and myocardium of heart grafts from wild type C57BL/6 mice, whereas grafts from GDF15 transgenic (TG) mice showed less damage as demonstrated by decreased cell apoptosis/death, decreased neutrophils infiltration and the preservation of the normal structure of the heart. Over-expression of GDF15 reduced expression of phosphorylated RelA p65, pre-inflammatory and pro-apoptotic genes while it enhanced Foxo3a phosphorylation in vitro and in vivo. Over-expression of GDF15 inhibited cell apoptosis/death and reduced neutrophil infiltration. In conclusion, this study, for the first time, demonstrates that GDF15 is a promising target for preventing cold I/R injury in heart transplantation. This study also shows that the resultant protective effects are mediated by the Foxo3 and NFκB signaling pathways.
- Subjects :
- Animals
Apoptosis genetics
Cytokines genetics
Cytokines metabolism
Humans
Inflammation Mediators metabolism
Male
Mice
Myocytes, Cardiac metabolism
Peroxidase metabolism
Phosphorylation
Rats
Reperfusion Injury prevention & control
Signal Transduction
Cold Ischemia adverse effects
Forkhead Box Protein O3 metabolism
Gene Expression
Growth Differentiation Factor 15 genetics
Heart Transplantation
Reperfusion Injury etiology
Reperfusion Injury metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1949-2553
- Volume :
- 8
- Issue :
- 22
- Database :
- MEDLINE
- Journal :
- Oncotarget
- Publication Type :
- Academic Journal
- Accession number :
- 28388574
- Full Text :
- https://doi.org/10.18632/oncotarget.16607