Abstract
BackgroundIn heart transplantation, donor hearts inevitably suffer from ischemia/reperfusion (I/R) injury, which leads to primary graft dysfunction and affects patients’ survival rate. Bone marrow mesenchymal stem cells (BMSCs) have been reported to attenuate myocardial I/R injury via their paracrine effects, which can be enhanced by hypoxic preconditioning. We hypothesized that the donor heart preservation with hypoxic conditioned medium (CdM) derived from BMSCs would improve post-transplant graft function.MethodsNormoxic or hypoxic CdM were isolated from rat BMSCs cultured under normoxic (20% O2) or hypoxic (1% O2) condition. Donor hearts were explanted; stored in cardioplegic solution supplemented with either a medium (vehicle), normoxic CdM (N-CdM), or hypoxic CdM (H-CdM); and then heterotopically transplanted. Antibody arrays were performed to compare the differences between hypoxic and normoxic CdM.ResultsAfter heart transplantation, the donor heart preservation with normoxic CdM was associated with a shorter time to return of spontaneous contraction and left ventricular systolic diameter, lower histopathological scores, higher ejection fraction, and fractional shortening of the transplanted hearts. The cardioprotective effects may be associated with the inhibition of apoptosis and inflammation, as reflected by less TUNEL-positive cells and lower levels of plasma proinflammatory cytokines (interleukin-1β, interleukin-6, tumor necrosis factor-α) and cardiac troponin I in the N-CdM group compared with the vehicle group. These therapeutic effects can be further enhanced by hypoxic preconditioning. Antibody arrays revealed that nine proteins were significantly increased in hypoxic CdM compared with normoxic CdM. Furthermore, compared with vehicle and N-CdM groups, the protein levels of PI3K and p-Akt/Akt ratio in the transplanted hearts significantly increased in the H-CdM group. However, no significant difference was found in the phosphorylation of Smad2 and Smad3 for the donor hearts among the three groups.ConclusionsOur results indicate that the cardioplegic solution-enriched with hypoxic CdM can be a novel and promising preservation solution for donor hearts.
Highlights
Heart transplantation remains a well-established therapy of choice for patients with refractory heart failure [1]
The cardioprotective effects may be associated with the inhibition of apoptosis and inflammation, as reflected by less transferase dUTP nick end labeling (TUNEL)-positive cells and lower levels of plasma proinflammatory cytokines and cardiac troponin I in the N-conditioned medium (CdM) group compared with the vehicle group
Our results indicate that the cardioplegic solution-enriched with hypoxic CdM can be a novel and promising preservation solution for donor hearts
Summary
Heart transplantation remains a well-established therapy of choice for patients with refractory heart failure [1]. The key mechanisms underlying myocardial I/R injury include increased intracellular calcium concentration, sudden generation of reactive oxygen species (ROS) and inflammatory cytokines, adenosine triphosphate (ATP) depletion, and development of metabolic acidosis. All of these factors are known to result in myocardial apoptosis [5] and the acceleration of allograft rejection or chronic allograft dysfunction. Attenuating myocardial I/R injury during the heart transplant procedure would have a favorable impact on improving short- and long-term graft function and recipient’s survival [6]. Donor hearts inevitably suffer from ischemia/reperfusion (I/R) injury, which leads to primary graft dysfunction and affects patients’ survival rate. We hypothesized that the donor heart preservation with hypoxic conditioned medium (CdM) derived from BMSCs would improve post-transplant graft function
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