Cardamonin attenuates cerebral ischemia/reperfusion injury by activating the HIF-1 alpha/VEGFA pathway
Cardamonin attenuates cerebral ischemia/reperfusion injury by activating the HIF-1 alpha/VEGFA pathway
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DOI：
10.1002/ptr.7409
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发表时间：
2022-02-10
影响因子：
7.2
通讯作者：
Zhou, Botao
中科院分区：
文献类型：
--
作者：
Ni, Hongzao;Li, Jinxiao;Zhou, Botao
豆蔻素是一种具有神经保护活性的查尔酮。本研究旨在探讨豆蔻甲素在缺血性卒中中的作用及作用机制。采用缺氧缺糖再灌注(OGD/R)诱导的人脑微血管内皮细胞(HBMECs)和大脑中动脉闭塞(MCAO)小鼠模型模拟缺血性卒中。用3-(4，5-dimethylthiazol-2-yl)-2，5-diphenyl-2H-tetrazolium溴化法分析细胞存活率。用异硫氰酸荧光素-葡聚糖比色法测定其通透性。TdT介导的dUTP缺口末端标记法检测细胞凋亡。用免疫印迹法检测缺氧诱导因子-1α和血管内皮生长因子A的蛋白水平。用2，3，5-三苯基四氮唑氯化铵染色、神经功能评分和脑含水量评价脑损伤。缺血性卒中和豆蔻素的37个重叠靶点被预测与HIF-1/VEGFA信号相关。豆蔻甲素可减轻OGD/R引起的HBMECs存活率下降、通透性增加和细胞凋亡。豆蔻碱能增加OGD/R诱导的HIF-1α/VEGFA通路的激活。用抑制剂抑制HIF-1α/VEGFA信号转导通路可减轻豆蔻碱致缺氧/再灌注小鼠脑损伤，促进HIF-1α/NEGFA信号转导通路的激活，从而减轻OGD/R状态下HIF-1α/VEGFA信号转导通路的损伤。总体而言，豆蔻素通过激活HIF-1α/VEGFA通路对OGD/R诱导的HBMEC损伤和MACO诱导的脑损伤具有保护作用。
Cardamonin is a chalcone with neuroprotective activity. The aim of our study was to explore the functions and mechanism of action of cardamonin in ischemic stroke. Oxygen-glucose deprivation and reperfusion (OGD/R)-induced human brain microvascular endothelial cells (HBMECs) and middle cerebral artery occlusion (MCAO) mouse model were utilized to mimic ischemic stroke. Cell viability was analyzed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide. Permeability was investigated via fluorescein isothiocyanate-dextran assay. Apoptosis was detected by TdT-Mediated dUTP Nick End Labeling staining. Hypoxia-inducible factor (HIF)-1 alpha and vascular endothelial growth factor A (VEGFA) protein levels were measured using Western blotting. Brain injury was evaluated by 2,3,5-triphenyltetrazolium chloride staining, neurological score and brain water content. The 37 overlapping targets of ischemic stroke and cardamonin were predicted to be associated with the HIF-1/VEGFA signaling. Cardamonin alleviated OGD/R-induced viability reduction and increase of permeability and apoptosis in HBMECs. Cardamonin increased OGD/R-induced activation of the HIF-1 alpha/VEGFA pathway. Inhibition of the HIF-1 alpha/VEGFA signaling using inhibitor relieved the effect of cardamonin on cell viability, permeability and apoptosis in HBMECs under OGD/R. Cardamonin mitigated brain injury and promoted activation of the HIF-1 alpha/NEGFA signaling in MCAO-treated mice. Overall, cardamonin protected against OGD/R-induced HBMEC damage and MACO-induced brain injury through activating the HIF-1 alpha/VEGFA pathway.