Apoptosis Antagonizing Transcription Factor Plays a Dual Role in Remote Preconditioning-Induced Neuroprotection Against Cerebral Ischemia/Reperfusion Injury in Aged Rats

Abstract The elderly population is increasingly susceptible to cerebral ischemia/reperfusion (I/R) injury. Although the potential protective effects of remote preconditioning (RPC) against cerebral ischemia have been explored, there is a paucity of research assessing its influence on elderly individuals. The role of apoptosis antagonizing transcription factor (AATF) in regulating neuronal activity has been reported, but the relationship between AATF and the effects of RPC remain unknown. To investigate the functions of RPC and AATF in cerebral I/R injury in the elderly, we employed aged rats and built models of PRC and cerebral I/R injury and constructed lentiviral Aatf-shRNA vectors. Results showed that RPC reduced brain infarct volume and improved neurological function in aged rats with cerebral I/R injury. Knocking-down AATF suppressed the protective effects of RPC. To investigate the role of AATF in RPC, oxygen glucose deprivation/reoxygenation (OGD/R) model and OGD preconditioning were conducted in vitro. Results showed that OGD preconditioning ameliorated OGD/R-induced cellular DNA fragmentation. AATF contributed to the effects of OGD preconditioning by regulating the cleavage of caspase-3 and modulating the interaction between nuclear apoptosis inducing factors (AIF) and H2AX. Finally, returning to an in vivo setting confirms the role of AATF in RPC. This study highlights the neuroprotective efficacy of RPC in alleviating cerebral I/R injury in aged rodents. Mechanistically, we identify that this protection is mediated by the activation of AATF. Collectively, our results suggest RPC holds promise as a therapeutic strategy to mitigate the detrimental effects of reperfusion therapy in geriatric populations. Notably, AATF exhibits dual regulatory functions in RPC-induced neuroprotection.