title: Over-expression of growth differentiation factor 15 (GDF15) preventing cold ischemia reperfusion (I/R) injury in heart transplantation through Foxo3a signaling.
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.
authors.affiliation: Department of Cardiovascular Surgery, The Second Hospital, Jilin University, Changchun, China.|Department of Pathology, Western University, Ontario, Canada.
authors.forename: Yixin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Western University, Ontario, Canada.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Moszczynski
authors.affiliation: Department of Cardiovascular Surgery, The Second Hospital, Jilin University, Changchun, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Pathology, Western University, Ontario, Canada.
authors.forename: Jifu
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Department of Cardiovascular Surgery, The Second Hospital, Jilin University, Changchun, China.|Department of Pathology, Western University, Ontario, Canada.
authors.forename: Duo
authors.initials: D
authors.lastname: Zhao
authors.affiliation: Department of Surgery, Western University, Ontario, Canada.|Lawson Health Research Institute, Ontario, Canada.|London Health Sciences Centre, Ontario, Canada.
authors.forename: Douglas
authors.initials: D
authors.lastname: Quan
authors.affiliation: Department of Surgery, Western University, Ontario, Canada.|London Health Sciences Centre, Ontario, Canada.
authors.forename: Tina
authors.initials: T
authors.lastname: Mele
authors.affiliation: Department of Surgery, Western University, Ontario, Canada.|Lawson Health Research Institute, Ontario, Canada.|London Health Sciences Centre, Ontario, Canada.
authors.forename: Vivian
authors.initials: V
authors.lastname: McAlister
authors.affiliation: Lawson Health Research Institute, Ontario, Canada.|London Health Sciences Centre, Ontario, Canada.|Department of Medicine, Western University, Ontario, Canada.|Matthew Mailing Centre, London Health Sciences Centre, Ontario, Canada.
authors.forename: Anthony
authors.initials: A
authors.lastname: Jevnikar
authors.affiliation: Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, TN, USA.
authors.forename: Seung Joon
authors.initials: SJ
authors.lastname: Baek
authors.affiliation: Department of Cardiovascular Surgery, The Second Hospital, Jilin University, Changchun, China.
authors.forename: Kexiang
authors.initials: K
authors.lastname: Liu
authors.affiliation: Department of Pathology, Western University, Ontario, Canada.|Department of Surgery, Western University, Ontario, Canada.|Lawson Health Research Institute, Ontario, Canada.|London Health Sciences Centre, Ontario, Canada.
authors.forename: Xiufen
authors.initials: X
authors.lastname: Zheng
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D050377:Cold Ischemia / Q000009:adverse effects*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D000071316:Forkhead Box Protein O3 / Q000378:metabolism*; D015870:Gene Expression; D055436:Growth Differentiation Factor 15 / Q000235:genetics*; D016027:Heart Transplantation; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D051379:Mice; D032383:Myocytes, Cardiac / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D015427:Reperfusion Injury / Q000209:etiology* / Q000378:metabolism* / Q000517:prevention & control; D015398:Signal Transduction
chemical_list: D016207:Cytokines; D000071316:Forkhead Box Protein O3; D055436:Growth Differentiation Factor 15; D018836:Inflammation Mediators; D009195:Peroxidase
keywords: Foxo3a; GDF15; heart transplantation; ischemia reperfusion injury