| Autor: |
Lei, Ienglam, Huang, Wei, Noly, Pierre Emmanuel, Naik, Suyash, Ghali, Miriyam, Liu, Liu, Pagani, Francis D., Abou El Ela, Ashraf, Pober, Jordan S., Pitt, Bertram, Platt, Jeffrey L., Cascalho, Marilia, Wang, Zhong, Chen, Y. Eugene, Mortensen, Richard M., Tang, Paul C. |
| Předmět: |
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| Zdroj: |
Science Translational Medicine; 2/8/2023, Vol. 15 Issue 682, p1-14, 14p |
| Abstrakt: |
Preservation quality of donor hearts is a key determinant of transplant success. Preservation duration beyond 4 hours is associated with primary graft dysfunction (PGD). Given transport time constraints, geographical limitations exist for donor-recipient matching, leading to donor heart underutilization. Here, we showed that metabolic reprogramming through up-regulation of the enzyme immune response gene 1 (IRG1) and its product itaconate improved heart function after prolonged preservation. Irg1 transcript induction was achieved by adding the histone deacetylase (HDAC) inhibitor valproic acid (VPA) to a histidine-tryptophan-ketoglutarate solution used for donor heart preservation. VPA increased acetylated H3K27 occupancy at the IRG1 enhancer and IRG1 transcript expression in human donor hearts. IRG1 converts aconitate to itaconate, which has both anti-inflammatory and antioxidant properties. Accordingly, our studies showed that Irg1 transcript up-regulation by VPA treatment increased nuclear translocation of nuclear factor erythroid 2–related factor 2 (Nrf2) in mice, which was accompanied by increased antioxidant protein expression [hemeoxygenase 1 (HO1) and superoxide dismutase 1 (SOD1)]. Deletion of Irg1 in mice (Irg1−/−) negated the antioxidant and cardioprotective effects of VPA. Consistent with itaconate's ability to inhibit succinate dehydrogenase, VPA treatment of human hearts increased itaconate availability and reduced succinate accumulation during preservation. VPA similarly increased IRG1 expression in pig donor hearts and improved its function in an ex vivo cardiac perfusion system both at the clinical 4-hour preservation threshold and at 10 hours. These results suggest that augmentation of cardioprotective immune-metabolomic pathways may be a promising therapeutic strategy for improving donor heart function in transplantation. Extending the shelf life of donor hearts: Organ transplantation is a life-saving procedure for many diseases but is hindered by strict time limits on ischemia to preserve donor tissue integrity. Here Lei et al. demonstrated that perfusion of human, mouse or pig hearts with the histone deacetylase inhibitor valproic acid could substantially extend cold storage time without compromising cardiac function. Metabolic and gene expression analysis indicated that valproic acid administration increased immune response gene 1 (IRG1) and its product itaconate, which led to reduced inflammation and oxidative stress. These results suggest that regulation of cellular metabolism through pharmacological treatment may be a potential way to improve donor organ preservation for transplantation. —AW [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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