微小RNA-452-3p靶向组蛋白去乙酰化酶3以抑制p65去乙酰化并激活蛛网膜下腔出血后早期脑损伤中的核因子κB信号通路。
miR-452-3p Targets HDAC3 to Inhibit p65 Deacetylation and Activate the NF-κB Signaling Pathway in Early Brain Injury after Subarachnoid Hemorrhage.
作者信息
Lu Junti, Huang Xiaodong, Deng Aiping, Yao Hong, Wu Gao, Wang Na, Gui Hui, Ren Mojie, Guo Shiwen
机构信息
Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an, 710061, Shaanxi, People's Republic of China.
Department of Neurosurgery, Taihe Hospital, Hubei University of Medicine, 32 People's South Road, Shiyan, 442000, Hubei, People's Republic of China.
出版信息
Neurocrit Care. 2022 Oct;37(2):558-571. doi: 10.1007/s12028-022-01509-z. Epub 2022 Jun 1.
OBJECTIVES
Subarachnoid hemorrhage (SAH) is a subtype of stroke, and early brain injury (EBI) is a contributor to its unfavorable outcome. microRNA (miRNA) is abundantly expressed in the brain and participates in brain injury. This study investigated the effect of miR-452-3p on EBI after SAH.
METHODS
The murine model of SAH was established. miR-452-3p expression was detected 48 h after the model establishment. Neurobehavioral function, blood-brain barrier permeability, brain water content, neuronal apoptosis, and inflammatory factors were evaluated. The cell model of SAH was induced by oxygen hemoglobin. Apoptosis rate, lactate dehydrogenase, and reactive oxygen species were detected. The targeting relationship between miR-452-3p and histone deacetylase 3 (HDAC3) was verified. The acetylation of p65 and the binding of HDAC3 to p65 were detected. The inhibitory protein of the nuclear factor κB pathway (IκBα) was detected. Suberoylanilide hydroxamic acid was injected into the SAH mice treated with miR-452-3p inhibitor.
RESULTS
SAH mice showed upregulated miR-452-3p expression; reduced the neurological score; increased blood-brain barrier permeability, brain water content, and neuronal apoptosis; elevated pro-inflammatory factors; and reduced anti-inflammatory factors. SAH increased the apoptosis rate, lactate dehydrogenase release, and reactive oxygen species levels in oxygen-hemoglobin-treated neuron cells. Inhibition of miR-452-3p reversed the above trends. miR-452-3p targeted HDAC3. SAH upregulated p65 acetylation. miR-452-3p inhibitor promoted the binding of HDAC3 to p65, decreased p65 acetylation, and upregulated IκBα. Suberoylanilide hydroxamic acid reversed the protective effect of miR-452-3p inhibitor on SAH mice and aggravated brain injury.
CONCLUSIONS
miR-452-3p targeted HDAC3 to inhibit the deacetylation of p65 and activate the nuclear factor κB pathway, thus aggravating EBI after SAH.
目的
蛛网膜下腔出血（SAH）是中风的一种亚型，早期脑损伤（EBI）是其不良预后的一个因素。微小RNA（miRNA）在大脑中大量表达并参与脑损伤。本研究调查了miR-452-3p对SAH后EBI的影响。
方法
建立SAH小鼠模型。在模型建立后48小时检测miR-452-3p表达。评估神经行为功能、血脑屏障通透性、脑含水量、神经元凋亡和炎症因子。用氧合血红蛋白诱导SAH细胞模型。检测凋亡率、乳酸脱氢酶和活性氧。验证miR-452-3p与组蛋白去乙酰化酶3（HDAC3）之间的靶向关系。检测p65的乙酰化以及HDAC3与p65的结合。检测核因子κB途径的抑制蛋白（IκBα）。将辛二酰苯胺异羟肟酸注射到用miR-452-3p抑制剂处理的SAH小鼠体内。
结果
SAH小鼠miR-452-3p表达上调；神经评分降低；血脑屏障通透性、脑含水量和神经元凋亡增加；促炎因子升高；抗炎因子降低。SAH增加了氧合血红蛋白处理的神经元细胞的凋亡率、乳酸脱氢酶释放和活性氧水平。抑制miR-452-3p可逆转上述趋势。miR-452-3p靶向HDAC3。SAH上调p65乙酰化。miR-452-3p抑制剂促进HDAC3与p65的结合，降低p65乙酰化，并上调IκBα。辛二酰苯胺异羟肟酸逆转了miR-452-3p抑制剂对SAH小鼠的保护作用并加重了脑损伤。
结论
miR-452-3p靶向HDAC3以抑制p65的去乙酰化并激活核因子κB途径，从而加重SAH后的EBI。
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