Overexpressed microRNA-539-5p inhibits inflammatory response of neurons to impede the progression of cerebral ischemic injury by histone deacetylase 1.

Several microRNAs (miRNAs or miRs) regulate cerebral ischemic injury outcomes; however, little is known about the role of miR-539-5p during cerebral ischemic injury or the post-ischemic state. Cerebral ischemic injury was modeled in vitro by exposing human cortical neurons to oxygen-glucose deprivation (OGD) and in vivo by occluding the middle cerebral artery (MCAO) in a rat model. The effects of miR-539-5p, histone deacetylase 1 (HDAC1), and early growth response 2 (EGR2) on cerebral ischemia were investigated using gain- and loss-of-function experiments. We identified changes in miR-539-5p, HDAC1, EGR2, and phosphorylated c-Jun N-terminal kinase (JNK). The interaction among miR-539-5p, HDAC1 and EGR2 was determined by dual luciferase reporter gene assay, chromatin immunoprecipitation and co-immunoprecipitation. We also investigated the effects on cell viability and apoptosis, changes in inflammatory cytokine expression and spatial memory on MCAO rats. miR-539-5p and EGR2 were poorly expressed, while HDAC1 was highly expressed in OGD-treated HCN-2 cells. miR-539-5p targeted HDAC1, while HDAC1 prevented acetylation of EGR2 resulting in its downregulation and subsequent activation of the JNK pathway. Overexpression of miR-539-5p or EGR2 or silencing HDAC1 improved viability and reduced apoptosis of OGD-treated HCN-2 cells in vitro. Furthermore, overexpression of miR-539-5p improved spatial memory, while decreasing cell apoptosis and inflammation in MCAO rats. Collectively, these data suggest that miR-539-5p targets HDAC1 to upregulate EGR2, thus blocking the JNK signaling pathway, by which cerebral ischemic injury is alleviated.