Over-expression of growth differentiation factor 15 (GDF15) preventing cold ischemia reperfusion (I/R) injury in heart transplantation through Foxo3a signaling
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Yixin Zhang1,2, Lisa A. Moszczynski2, Qing Liu1, Jifu Jiang2, Duo Zhao1,2, Douglas Quan3,4,5, Tina Mele3,5, Vivian McAlister3,4,5, Anthony Jevnikar4,5,6,7, Seung Joon Baek8, Kexiang Liu1 and Xiufen Zheng2,3,4,5
1Department of Cardiovascular Surgery, The Second Hospital, Jilin University, Changchun, China
2Department of Pathology, Western University, Ontario, Canada
3Department of Surgery, Western University, Ontario, Canada
4Lawson Health Research Institute, Ontario, Canada
5London Health Sciences Centre, Ontario, Canada
6Department of Medicine, Western University, Ontario, Canada
7Matthew Mailing Centre, London Health Sciences Centre, Ontario, Canada
8Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, TN, USA
Xiufen Zheng, email: email@example.com
Kexiang Liu, email: firstname.lastname@example.org
Keywords: GDF15, ischemia reperfusion injury, heart transplantation, Foxo3a
Received: January 10, 2017 Accepted: March 02, 2017 Published: March 27, 2017
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.
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