Electroacupuncture ameliorates blood-brain barrier disruption after ischemic stroke through histone acetylation regulation at the matrix metalloproteinase 9 and tissue inhibitor of metalloproteinase 2 genes

• Published in: Journal of traditional Chinese medicine Vol. 44; no. 4; pp. 734 - 744
• Main Authors: Yonglin, Chen, Ling, Ouyang, Lingling, Meng, Bufan, W U, Rou, Peng, Sitong, Liu, Dan, Hou, Yaling, Wang, Xinyue, Jing, Shengfeng, L U, Shuping, F U
• Format: Journal Article
• Language: English
• Published: China Editorial board of Journal of Traditional Chinese Medicine 01.08.2024
• Subjects: Acetylation; Animals; Blood-Brain Barrier - metabolism; Electroacupuncture; Histones - genetics; Histones - metabolism; Humans; Ischemic Stroke - genetics; Ischemic Stroke - metabolism; Ischemic Stroke - therapy; Male; Matrix Metalloproteinase 9 - genetics; Matrix Metalloproteinase 9 - metabolism; Original; Rats; Rats, Sprague-Dawley; Tissue Inhibitor of Metalloproteinase-2 - genetics; Tissue Inhibitor of Metalloproteinase-2 - metabolism; blood-brain barrier; electroacupuncture; tissue inhibitor of metalloproteinases; matrix metalloproteinase 9; histone acetylation
• ISSN: 0255-2922; 2589-451X
• DOI: 10.19852/j.cnki.jtcm.20240610.004

To explore whether the regulation of matrix metalloproteinase 9 (MMP-9)/ tissue inhibitors of MMPs (TIMPs) gene expression through histone acetylation is a possible mechanism by which electroacupuncture (EA) protects blood-brain barrier (BBB) integrity in a middle cerebral artery occlusion (MCAO) rat model. Male Sprague-Dawley rats were divided into four groups: the sham group, the MCAO group, the MCAO + EA (MEA) group, and the MCAO + EA + HAT inhibitor (HATi) group. The MCAO model was generated by blocking the middle cerebral artery. EA was applied to Baihui (GV20). Samples were collected 1 or 3 d after reperfusion. Neurological function scores and Evans blue extravasation were employed to evaluate the poststroke injury. The effect of EA on MMP-9/TIMPs gene expression was assessed by real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) and chromatin immunoprecipitation (ChIP). Our results showed that EA treatment prominently improved neurological function and ameliorated BBB disruption. The RT-qPCR assay showed that EA reduced the expression of MMP-9 and promoted TIMP-2 mRNA expression, but HATi reversed these effects of EA. In addition, ChIP results revealed that EA decreased the enrichment of H3K9ace/H3K27ace at MMP-9 promoters and notably stimulated the recruitment of H3K9ace/H3K27ace at TIMP-2 promoter. EA treatment at Baihui (GV20) regulates the transcription of MMP-9 and TIMP-2 through histone acetylation modification in the acute stage of stroke, which preserves the structural integrity of the BBB in MCAO rats. These findings suggested that the histone acetylation-mediated transcriptional activity of target genes may be a crucial mechanism of EA treatment in stroke.