Metabolic reprogramming by immune-responsive gene 1 up-regulation improves donor heart preservation and function.
Metabolic reprogramming by immune-responsive gene 1 up-regulation improves donor heart preservation and function.
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免疫应答基因1上调代谢重编程改善供体心脏保存和功能。
DOI：
10.1126/scitranslmed.ade3782
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发表时间：
2023-02-08
影响因子：
17.1
通讯作者：
Tang, Paul C.
中科院分区：
文献类型：
--
作者：
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.
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）有关。由于运输时间限制，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，我们表明，通过上调酶免疫反应基因1（IRG 1）及其产物衣康酸盐的代谢重编程改善了长期保存后的心脏功能。通过将组蛋白脱乙酰酶（HDAC）抑制剂丙戊酸（VPA）加入用于供体心脏保存的组氨酸-色氨酸-酮戊二酸溶液中，实现Irg 1转录诱导。VPA增加了人供体心脏中IRG 1增强子处的乙酰化H3 K27占用率和IRG 1转录表达。IRG 1将乌头酸转化为衣康酸，衣康酸具有抗炎和抗氧化特性。因此，我们的研究表明，VPA处理引起的Irg 1转录上调增加了小鼠核因子红细胞2相关因子2（Nrf 2）的核转位，并伴随着抗氧化蛋白表达[血红素加氧酶1（HO 1）和超氧化物歧化酶1（SOD 1）]的增加。在小鼠中缺失Irg 1（Irg 1 −/−）否定了VPA的抗氧化和心脏保护作用。与衣康酸盐抑制琥珀酸脱氢酶的能力一致，VPA处理人心脏增加了衣康酸盐的可用性，并减少了保存期间琥珀酸盐的积累。VPA同样增加了猪供体心脏中IRG 1的表达，并在临床4小时保存阈值和10小时时改善了其在离体心脏灌注系统中的功能。这些结果表明，心脏保护免疫代谢途径的增强可能是一个有前途的治疗策略，以改善移植供体心脏功能。
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.
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影响因子：
16
作者：
Calo, Eliezer;Wysocka, Joanna
通讯作者：
Wysocka, Joanna
DOI：
10.1016/b978-0-12-394309-5.00006-7
发表时间：
2012
影响因子：
--
作者：
Kalogeris, Theodore;Baines, Christopher P.;Krenz, Maike;Korthuis, Ronald J.
通讯作者：
Korthuis, Ronald J.
DOI：
10.1161/circheartfailure.115.002679
发表时间：
2016-04
期刊：
Circulation. Heart failure
影响因子：
--
作者：
Hsich EM
通讯作者：
Hsich EM
影响因子：
56.9
作者：
Chakraborty, Abhishek A.;Laukka, Tuomas;Kaelin, William G., Jr.
通讯作者：
Kaelin, William G., Jr.
影响因子：
64.8
作者：
Bambouskova M;Gorvel L;Lampropoulou V;Sergushichev A;Loginicheva E;Johnson K;Korenfeld D;Mathyer ME;Kim H;Huang LH;Duncan D;Bregman H;Keskin A;Santeford A;Apte RS;Sehgal R;Johnson B;Amarasinghe GK;Soares MP;Satoh T;Akira S;Hai T;de Guzman Strong C;Auclair K;Roddy TP;Biller SA;Jovanovic M;Klechevsky E;Stewart KM;Randolph GJ;Artyomov MN
通讯作者：
Artyomov MN