Targeted Activation of HNF4 & alpha; by AMPK Inhibits Apoptosis and Ameliorates Neurological Injury Caused by Cardiac Arrest in Rats

Previous studies have shown that AMPK plays an important role in cerebral ischemia-reperfusion injury by participating in apoptosis, but the exact mechanism and target of action remains unclear. This study aimed to investigate the protective mechanism of AMPK activation on brain injury secondary to cardiac arrest. HE, Nills and TUNEL assays were used to evaluate neuronal damage and apoptosis. The relationships between AMPK, HNF4a and apoptotic genes were verified by ChIP-seq, dual-luciferase and WB assays. The results showed that AMPK improved the 7-day memory function of rats, and reduced neuronal cell injury and apoptosis in the hippocampal CA1 region after ROSC, while the use of HNF4a inhibitor weakened the protective effect of AMPK. Further research found that AMPK positively regulated the expression of HNF4a, and AMPK could promote the expression of Bcl-2 and inhibit the expression of Bax and Cleaved-Caspase 3. In vitro experiments showed that AMPK ameliorated neuronal injury by inhibiting apoptosis through the activation of HNF4a. Combined with ChIP-seq, JASPAR analysis and Dual-luciferase assay, the binding site of HNF4a to the upstream promoter of Bcl-2 was found. Taken together, AMPK attenuates brain injury after CA by activating HNF4a to target Bcl-2 to inhibit apoptosis.

Automated summary

This study investigated the protective mechanism of AMPK activation on brain injury secondary to cardiac arrest. The results showed that AMPK improved memory function, reduced neuronal cell injury and apoptosis after resuscitation. Further research found that AMPK activated HNF4a to target Bcl-2 and inhibit apoptosis.