Abstract
Background: Cold ischemic storage and subsequent reperfusion injury contributes to the primary graft dysfunction after heart transplantation. Valproic acid (VPA) has been shown to reduce myocardial infarction injury. However, the role of VPA in donor heart preservation is unknown. Methods: We investigate the role of VPA on donor heart preservation using both ex-vivo perfusion and heterotopic transplantation in murine models. Results: Our results demonstrate the administration of VPA to histidine-tryptophan-ketoglutarate (HTK) cardioplegia can significantly improve donor heart function after perfusion with extend storage time (16 hours, n=8). Specifically, VPA reduced the accumulation of succinate, a metabolite that involved in reperfusion injury, during cold storage. We further show that VPA increases the Irg1 expression. Irg1 is known to produce itaconate and suppress the succinate accumulation during ischemia. We found that the effect of VPA in donor heart function is significantly reduced in Irg1 knockout mice compared to wild type mice after 16 hours of cold storage. Furthermore, VPA reduced oxidative stress of donor heart via Nrf2 antioxidant pathway activation. However, Irg1 deletion decreased the induction of antioxidant genes expression by VPA. Administration of 4-octyl-itaconate rescued donor heart function after extended storage. Conclusion: Our results demonstrate that VPA could improve donor heart function and ischemic tolerance. This is in part through Irg1/itaconate mediated anti-oxidative activities. Importantly, VPA preserved cardiac function after perfusion with extended storage times. This strategy can extend the tolerable ischemic time for donor heart for heart transplant and may reduce the incidence of primary graft dysfunction.
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