Donepezil ameliorates oxygen-glucose deprivation/reoxygenation-induced cardiac microvascular endothelial cell dysfunction through PARP1/NF-κB signaling

Ischemia/reperfusion (I/R) injury is a serious clinical condition characterized by high morbidity and mortality rates. Donepezil plays a neuroprotective role in I/R-associated diseases. The aim of the present study was to investigate the role and the potential mechanism of action of donepezil in I/R-induced myocardial microvascular endothelial cell dysfunction. An I/R model was simulated using oxygen-glucose deprivation/reoxygenation (OGD/R) injury in human cardiac microvascular endothelial cells (CMECs). Cell viability and lactate dehydrogenase release were examined following treatment with donepezil. Commercial kits were used to evaluate cell apoptosis, cell permeability and caspase-3 activity. The expression levels of apoptosis-associated proteins, as well as proteins found in tight junctions or involved in the poly(ADP-ribose) polymerase 1 (PARP1)/NF-kappa B pathway, were measured using western blotting. These parameters were also examined following PARP1 overexpression. The results demonstrated that donepezil increased cell viability and reduced toxicity in OGD/R-treated CMECs. The apoptotic rate, caspase-3 activity and protein expression levels of Bax and cleaved caspase-3 were significantly reduced following donepezil treatment, which was accompanied by Bcl-2 upregulation. Moreover, cell permeability was notably reduced, coupled with a marked increase in the expression of tight junction-associated proteins. The expression levels of proteins related to PARP1/NF-kappa B signaling were significantly downregulated in CMECs following donepezil treatment. However, the protective effects of donepezil on OGD/R-induced CMEC injury were reversed following PARP1 overexpression. In conclusion, donepezil suppressed OGD/R-induced CMEC dysfunction via PARP1/NF-kappa B signaling. This finding provided insight into the mechanism underlying myocardial I/R injury.

Automated summary

Donepezil can alleviate ischemia/reperfusion (I/R) injury by suppressing myocardial microvascular endothelial cell dysfunction through the PARP1/NF-κB signaling pathway.