The Ketone Metabolite β-Hydroxybutyrate Attenuates Oxidative Stress in Spinal Cord Injury by Suppression of Class I Histone Deacetylases
The Ketone Metabolite β-Hydroxybutyrate Attenuates Oxidative Stress in Spinal Cord Injury by Suppression of Class I Histone Deacetylases
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DOI：
10.1089/neu.2017.5192
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发表时间：
2017-09-15
影响因子：
4.2
通讯作者：
Zhu, Qingan
中科院分区：
文献类型：
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作者：
Kong, Ganggang;Huang, Zucheng;Zhu, Qingan
据报道，酮代谢物β -羟基丁酸（β OHB）在大鼠脊髓损伤（SCI）后具有神经保护作用，但其潜在机制尚不清楚。本研究旨在探讨β OHB在体内和体外模型中对氧化应激和I类组蛋白去乙酰化酶（hdac）的抑制作用。大鼠分别饲喂生酮饮食（KD）和标准饮食（SD） 3周。实验第14天对这些动物进行C5半挫伤，分别于脊髓损伤后第1天、第3天和第7天采集脊髓样本。KD组血酮水平显著升高。KD降低了氧化应激标志物和活性氧（ROS）产物，下调了烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶（NOX） 2和NOX4的表达，上调了脑损伤后叉头盒组O (FOXO)3a、线粒体超氧化物歧化酶（MnSOD）和过氧化氢酶的表达。在PC12细胞上进行的体外研究表明，β OHB抑制h2o2诱导的ROS生成，降低NOX2和NOX4蛋白水平，上调FOXO3a、MnSOD和过氧化氢酶水平，且呈剂量依赖性，与体内结果一致。在SCI大鼠和PC12细胞中，酮代谢物β OHB抑制HDAC1、HDAC2和HDAC3活性，但不抑制HDAC8活性。用小干扰RNA （siRNA）去除HDAC1或HDAC2可减弱h2o2诱导的ROS生成和蛋白羰基化，提高FOXO3a蛋白水平，同时降低PC12细胞中NOX2和NOX4蛋白的表达。我们的研究结果表明，酮代谢物β OHB通过抑制I类hdac来减轻SCI中的氧化应激，选择性抑制HDAC1或HDAC2可调节FOXO3a、NOX2和NOX4的表达。因此，酮代谢物β OHB可能是一种新的有前景的治疗脊髓损伤的药物。
The ketone metabolite beta-hydroxybutyrate (beta OHB), is reported to be neuroprotective after spinal cord injury (SCI) in rats, but the underlying mechanism remains unknown. The present study aims to investigate effects of beta OHB on suppression of oxidative stress and inhibition of class I histone deacetylases (HDACs) in in vivo and in vitro models. Rats were fed with ketogenic diet (KD) or standard diet (SD) for 3 weeks. A C5 hemi-contusion injury was applied to these animals on the 14th day of experiment, and spinal cord samples were harvested on the 1st, 3rd and 7th days after SCI, respectively. The blood ketone levels were significantly higher in the KD groups. KD reduced oxidative stress markers and reactive oxygen species (ROS) products, downregulated the expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) 2 and NOX4, and upregulated the expression of forkhead box group O (FOXO)3a, mitochondrial superoxide dismutase (MnSOD), and catalase after SCI. The in vitro study, performed on PC12 cells, indicated that beta OHB inhibited H2O2-induced ROS production, decreased NOX2 and NOX4 protein levels, and upregulated FOXO3a, MnSOD, and catalase levels in a dose-dependent manner, which was consistent with the in vivo results. The ketone metabolite beta OHB inhibited HDAC1, HDAC2, and HDAC3 activity, but not HDAC8 in SCI rats and PC12 cells. Depletion of HDAC1 or HDAC2 with small interfering RNA (siRNA) attenuated H2O2-induced ROS production and protein carbonylation and elevated FOXO3a protein levels, meanwhile reducing NOX2 and NOX4 protein expression in PC12 cells. Our results indicate that the ketone metabolite beta OHB attenuates oxidative stress in SCI by inhibition of class I HDACs, and selected suppression of HDAC1 or HDAC2 regulates FOXO3a, NOX2, and NOX4 expression. Therefore, the ketone metabolite beta OHB may be a novel promising therapeutic agent for SCI.