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.

中文翻译：

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通过免疫反应基因 1 上调进行的代谢重编程可改善供体心脏的保存和功能

供体心脏的保存质量是移植成功的关键决定因素。保存时间超过 4 小时与原发性移植物功能障碍 (PGD) 相关。鉴于运输时间的限制，供体-受体匹配存在地理限制，导致供体心脏利用不足。在这里，我们发现通过上调酶免疫反应基因 1 (IRG1) 及其产物衣康酸盐进行代谢重编程可在长期保存后改善心脏功能。Irg1通过将组蛋白去乙酰化酶 (HDAC) 抑制剂丙戊酸 (VPA) 添加到用于供体心脏保存的组氨酸-色氨酸-酮戊二酸溶液中来实现转录诱导。VPA 增加了乙酰化 H3K27 在IRG1增强子和IRG1人类供体心脏中的转录物表达。IRG1 将乌头酸转化为衣康酸，后者具有抗炎和抗氧化特性。因此，我们的研究表明Irg1VPA 处理的转录上调增加了小鼠核因子红细胞 2 相关因子 2 (Nrf2) 的核转位，同时伴随着抗氧化蛋白表达的增加 [血红素加氧酶 1 (HO1) 和超氧化物歧化酶 1 (SOD1)]。删除Irg1在小鼠中（Irg1-/-) 否定了 VPA 的抗氧化和心脏保护作用。与衣康酸抑制琥珀酸脱氢酶的能力一致，VPA 处理人类心脏增加了衣康酸的可用性并减少了保存过程中的琥珀酸积累。VPA同样增加IRG1在猪供体心脏中表达，并在临床 4 小时保存阈值和 10 小时时改善其在离体心脏灌注系统中的功能。这些结果表明，增强心脏保护性免疫代谢组学途径可能是改善移植供体心脏功能的有前途的治疗策略。