Silencing of microRNA‐494 inhibits the neurotoxic Th1 shift via regulating HDAC2‐STAT4 cascade in ischaemic stroke

• DOI: 10.1111/bph.14852
• Publication Date: 2019-08-29T17:01:50Z
• Authors: Haiping Zhao; Guangwen Li; Rongliang Wang; Zhen Tao; Qingfeng Ma; Sijia Zhang; Ziping Han; Feng Yan; Fangfang Li; Ping Liu; Shubei Ma; Xunming Ji; Yumin Luo
• Keywords: Histone deacetylase 2; Histone deacetylase inhibitor

Background and Purpose T helper cell 1 (Th1)‐skewed neurotoxicity contributes to the poor outcome of stroke in rodents. Here, we have elucidated mechanism Th1/Th2 shift acute ischaemic (AIS) patients at hyperacute phase looked for a miRNA‐based therapeutic target. Experimental Approach MiR‐494 levels blood from AIS controls were measured by real‐time PCR. C57BL/6J mice subjected transient middle cerebral artery occlusion, cortical neurons oxygen–glucose deprivation. Luciferase reporter system, chromatin immunoprecipitation sequencing (ChIP‐Seq), ChIP‐PCR used uncover possible mechanisms. Key Results In lymphocytes patients, there was histone deacetylase 2 (HDAC2) markedly down‐regulated. ChIP‐seq showed that HDAC2 binding sites enriched regulation Th1 cytokine production, confirmed changed intron STAT4 promoter T‐box transcription factor 21 (T‐bet) patients. most significantly increased miRNA miR‐494‐3p directly targeted HDAC2. A strong association existed between miR‐494 cytokines, neurological deficit as National Institute Health Stroke Scale (NIHSS) vitro vivo experiments antagomir‐494 reduced shift‐mediated neuronal sensorimotor functional damage mouse model stroke, via HDAC2‐STAT4 pathway. Conclusion Implications We demonstrated inhibition prevented ‐ skewed through cascade.