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

Br J Pharmacol. 2020 Jan;177(1):128-144. doi:10.1111/bph.14852. Epub 2019 Nov 08
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摘要


BACKGROUND AND PURPOSE:T helper cell 1 (Th1)-skewed neurotoxicity contributes to the poor outcome of stroke in rodents. Here, we have elucidated the mechanism of the Th1/Th2 shift in acute ischaemic stroke (AIS) patients at hyperacute phase and have looked for a miRNA-based therapeutic target. EXPERIMENTAL APPROACH:MiR-494 levels in blood from AIS patients and controls were measured by real-time PCR. C57BL/6J mice were subjected to transient middle cerebral artery occlusion, and cortical neurons were subjected to oxygen-glucose deprivation. Luciferase reporter system, chromatin immunoprecipitation sequencing (ChIP-Seq), and ChIP-PCR were used to uncover possible mechanisms. KEY RESULTS:In lymphocytes from AIS patients, there was a Th1/Th2 shift and histone deacetylase 2 (HDAC2) was markedly down-regulated. ChIP-seq showed that HDAC2 binding sites were enriched in regulation of Th1 cytokine production, and ChIP-PCR confirmed that HDAC2 binding was changed at the intron of and the promoter of T-box transcription factor 21 (T-bet) in lymphocytes from AIS patients. MiR-494 was the most significantly increased miRNA in lymphocytes from AIS patients, and miR-494-3p directly targeted HDAC2. A strong association existed between miR-494 and Th1 cytokines, and neurological deficit as measured by the National Institute of Health Stroke Scale (NIHSS) in AIS patients. In vitro and in vivo experiments showed that antagomir-494 reduced Th1 shift-mediated neuronal and sensorimotor functional damage in the mouse model of ischaemic stroke, via the pathway. CONCLUSION AND IMPLICATIONS:We demonstrated that miR-494 inhibition prevented Th1-skewed neurotoxicity through regulation of the HDAC2-duanyu18134 cascade.

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