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

Abstract

Heart transplant has been accepted as the standard treatment for end-stage heart failure. Because of its susceptibility to ischemia-reperfusion injury, the heart can be preserved for only 4 to 6 hours in cold static preservation solutions. Prolonged ischemia time is adversely associated with primary graft function and long-term survival. New strategies to preserve donor hearts are urgently needed. We demonstrate that AP39, a mitochondria-targeting hydrogen sulfide donor, significantly increases cardiomyocyte viability and reduces cell apoptosis/death after cold hypoxia/reoxygenation in vitro. It also decreases gene expression of proinflammatory cytokines and preserves mitochondria function. Using an in vivo murine heart transplant model, weshow that preserving donor hearts with AP39-supplemented University of Wisconsin solution (n = 7) significantly protects heart graft function, measured by quantitative ultrasound scan, against prolonged cold ischemia-reperfusion injury (24 hours at 4°C), along with reducing tissue injury and fibrosis. Our study demonstrates that

Preventing alloimmune rejection using circular RNA FSCN1-silenced dendritic cells in heart transplantation

“…The heart from a fully major histocompatibility complex (MHC) mismatched C57BL/6 donor mouse was transplanted into the abdomen of the recipient mouse following our previously established procedure. 13,[21][22][23][24] After transplantation, the recipient mice received daily sub-dose rapamycin (1 mg/kg; LC Laboratories, Woburn, MA) through intra-peritoneal (I.P.) injection from day 0 to 7.…”

The Potential of Hydrogen Sulfide Donors in Treating Cardiovascular Diseases

“…A DTT derivative of the triphenyl brominated tail, known as AP39, has also been synthesized. AP39 has mitochondrial targeting and antioxidant activities that could maintain cellular homeostasis by inhibiting the activation of the mitochondrial death pathway [ 62 , 63 ]. AP39 can not only significantly increase the viability of cardiomyocytes, but can also decrease apoptosis after cold hypoxia/reoxygenation, which has therapeutic potential in heart transplantation [ 62 , 63 ].…”

“…AP39 has mitochondrial targeting and antioxidant activities that could maintain cellular homeostasis by inhibiting the activation of the mitochondrial death pathway [ 62 , 63 ]. AP39 can not only significantly increase the viability of cardiomyocytes, but can also decrease apoptosis after cold hypoxia/reoxygenation, which has therapeutic potential in heart transplantation [ 62 , 63 ]. In addition, a novel donor NOSH-NBP has recently been synthesized from the mixture of NO and H 2 S, and the compound can significantly reduce the infarct volume and improve neurological deficits compared to NO-NBP or H 2 S-NBP in microglia cells and a mouse model [ 64 ].…”

Genetic Engineering of the Kidney to Permanently Silence MHC Transcripts During ex vivo Organ Perfusion

“…The impact of this change in the cytokine secretion pattern in the transplantation outcome needs to be investigated in detail in future experiments. Currently, different approaches to prevent the release of pro-inflammatory cytokines by ex vivo perfused organs based on the use of membranes or small molecules are being developed to avoid tissue impairment during perfusion or the activation and polarization of immune responses after transplantation (54,55).…”