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.

GDF15 Regulates Malat-1 Circular RNA and Inactivates NFκB Signaling Leading to Immune Tolerogenic DCs for Preventing Alloimmune Rejection in Heart Transplantation

“…Nuclear factor-kappa B (NFκB) is essential for DC maturation ( 29 ) and interruption of the pathway will impair the maturation of DCs and their function ( 30 ). There are some contradictory reports on whether GDF15 inhibits vs. activates the NFκB pathway ( 31 , 32 , 33 ). Nevertheless, the relationship between GDF15 and NFκB signal in DCs remains unknown.…”

Supplementing preservation solution with mitochondria-targeted H2S donor AP39 protects cardiac grafts from prolonged cold ischemia–reperfusion injury in heart transplantation

“…For PCMs, a previously established H/R condition (0% O 2 for 16 hrs at 10°C with 6 hours reoxygenation at 37°C) was used . Briefly, PCMs with 100 nmol/L AP39–supplemented PBS were placed in hypoxia bags for 16 hours at 10°C, followed by 6 hours of reoxygenation in DMEM with 100 nmol/L AP39 in the normal cell culture conditions.…”

“…Heart grafts were collected from mice on postoperative day (POD) 7. Fixed heart tissues were sectioned and stained with hematoxylin and eosin or Trichrome Staining Kit (Abcam Inc.) . The histological changes were determined by a qualified pathologist in a blind manner.…”

The MIC-1/GDF15-GFRAL Pathway in Energy Homeostasis: Implications for Obesity, Cachexia, and Other Associated Diseases

“…This question, however, may be informed by studies of MIC-1/GDF15 in inflammatory disease in which its tissue expression and serum level rise. The majority of studies of animal models of inflammation, some of which will be discussed in more detail below, strongly suggests that MIC-1/GDF15 has an overall beneficial effect on disease outcome (Johnen et al, 2012;Preusch et al, 2013;Kempf et al, 2006Kempf et al, , 2011Zhang et al, 2017;Mensching et al, 2012;Wang et al, 2015b;…”

“…Further, following transient coronary artery ligation, MIC-1/GDF15 KO mice displayed an increased infarct size with more cardiomyocyte apoptosis (Kempf et al, 2006). Conversely, overexpression of MIC-1/ GDF15 prevented cold ischemia-reperfusion injury of transplanted hearts that displayed decreased cellular apoptosis and neutrophil infiltration, perhaps by reducing the expression of pro-inflammatory phosphorylated RelA p65 (Zhang et al, 2017). Complete coronary artery ligation in MIC1/GDF15-deficient mice led to enhanced recruitment of neutrophils into the infarcted myocardium and an increased incidence of cardiac rupture (Kempf et al, 2011).…”