Endoplasmic reticulum stress regulates oxygen-glucose deprivation-induced parthanatos in human SH-SY5Y cells via improvement of intracellular ROS.

Abstract

Endoplasmic reticulum (ER) stress has been demonstrated to regulate neuronal death caused by ischemic insults via activation of apoptosis, but it still remains unclear whether ER stress participates in regulation of parthanatos, a new type of programmed cell death characterized by PARP-1 overactivation and intracellular accumulation of PAR polymer. we used oxygen-glucose deprivation (OGD) and human SH-SY5Y cells to simulate neuronal damage caused by ischemia. Oxygen-glucose deprivation induced time-dependent death in SH-SY5Y cells, which was accompanied with upregulation of PARP-1, accumulation of PAR polymer, decline of mitochondrial membrane potentials and nuclear translocation of AIF. Pharmacological inhibition of PARP-1 with its specific inhibitor 3AB rescued OGD-induced cell death, as well as prevented PAR polymer accumulation, mitochondrial depolarization, and AIF translocation into nucleus. Similar results could be found when PARP-1 was genetically knocked down with SiRNA. These indicated that OGD triggered parthanatos in SH-SY5Y cells. Then, we found inhibition of overproduction of ROS with antioxidant NAC attenuated obviously OGD-induced parthanatos in SH-SY5Y cells, suggesting ROS regulated OGD-induced parthanatos. Additionally, OGD also induced upregulation of ER stress-related proteins. Mitigation of ER stress with chemical chaperone 4-PBA or trehalose suppressed significantly OGD-induced overproduction of ROS, PARP-1 upregulation, PAR polymer accumulation, and nuclear accumulation of AIF, and cell death in SH-SY5Y cells. Endoplasmic reticulum stress regulates OGD-induced parthanatos in human SH-SY5Y cells via improvement of intracellular ROS.