Downregulation of miR-26b attenuates early brain injury induced by subarachnoid hemorrhage via mediating the KLF4/STAT3/HMGB1 axis.

BACKGROUND

Early brain injury (EBI) refers to early-onset secondary complications that occur after subarachnoid hemorrhage (SAH), and associated with high rate of disability and mortality. Recent investigations have indicated microRNA-26b (miR-26b) as a biomarker in the progression of SAH. Accordingly, the present study was designed to elucidate the role of miR-26b in influencing EBI following SAH and the downstream mechanisms.

METHODS

Firstly, SAH rat models and neuron injury models were developed to assess the effect of miR-26b on EBI-like symptoms and subsequent inflammation. Dual-luciferase reporter gene assay was further implemented to evaluate the binding of miR-26b to its putative target gene STAT3. Loss-of-function and rescue experiments were performed to assess the functionality of miR-26b-mediated STAT3 in both models.

RESULTS

miR-26b was found to target KLF4 and negative-modulate its expression, whereby aggravating EBI and inflammatory response in SAH rat models and stimulating hemoglobin-induced apoptosis in astrocytes. On the other hand, silencing of miR-26b reversed these changes in SAH rat models and hemoglobin (Hb)-induced astrocytes. miR-26b could further activate STAT3 via down-regulation of KLF4. Furthermore, KLF4 knockdown up-regulated HMGB1 to aggravate EBI following SAH.

CONCLUSIONS

Collectively, our findings highlighted the ameliorative effect of miR-26b inhibition on EBI in SAH and the possible mechanism associated with the KLF4/STAT3/HMGB1 axis.