组蛋白去乙酰化酶1（HDAC1）通过使Nur77去乙酰化破坏三羧酸（TCA）循环，并促进缺血再灌注小鼠的炎症反应。

HDAC1 disrupts the tricarboxylic acid (TCA) cycle through the deacetylation of Nur77 and promotes inflammation in ischemia-reperfusion mice.

作者信息

Wu Zhenhua, Bai Yunpeng, Qi Yujuan, Chang Chao, Jiao Yan, Bai Yaobang, Guo Zhigang

机构信息

Academy of Medical Engineering and Translational Medicine, Tianjin University, 300222, Tianjin, China.

ICU, Department of Cardiac Surgery, Tianjin Chest Hospital, 300222, Tianjin, China.

出版信息

Cell Death Discov. 2023 Jan 18;9(1):10. doi: 10.1038/s41420-023-01308-1.

Histone deacetylase enzymes (HDACs) regulate protein acetylation. HDAC1 is known to enhance ischemia/reperfusion (I/R) injury, but its underlying mechanism(s) of action have not been defined. Here, in vivo mouse models of myocardial I/R were used to investigate the role of HDAC1 during I/R myocardial injury. We show that HDAC1 enhances the inflammatory responses of I/R mice. Using a constructed macrophage H/R (hypoxia/ regeneration) injury model (Raw264.7 cells), we identified Nur77 as a HDAC1 target in macrophages. Nur77 deficient macrophages failed to downregulate IDH1 (isocitrate dehydrogenase 1) and accumulated succinic acid and other tricarboxylic acid (TCA) cycle-derived metabolites in a glutamine-independent manner. These data show that the inhibition of HDAC1 ameliorates H/R-inflammation in macrophages through the regulation of Nur77 and the TCA cycle.

组蛋白去乙酰化酶（HDACs）调节蛋白质乙酰化。已知HDAC1会加重缺血/再灌注（I/R）损伤，但其潜在作用机制尚未明确。在此，我们使用心肌I/R的体内小鼠模型来研究HDAC1在I/R心肌损伤中的作用。我们发现HDAC1会增强I/R小鼠的炎症反应。通过构建巨噬细胞H/R（缺氧/复氧）损伤模型（Raw264.7细胞），我们确定Nur77是巨噬细胞中HDAC1的一个靶点。Nur77缺陷型巨噬细胞无法下调异柠檬酸脱氢酶1（IDH1），并以不依赖谷氨酰胺的方式积累琥珀酸和其他三羧酸（TCA）循环衍生的代谢物。这些数据表明，抑制HDAC1可通过调节Nur77和TCA循环改善巨噬细胞中的H/R炎症。