Heme induces autophagic cell death via ER stress in neuron

Abstract

Aims Intracerebral hemorrhage (ICH) is serious medical problem and the effective treatment is limited. Hemorrhaged blood is highly toxic to the brain, and heme mainly released from hemoglobin plays a vital role in neurotoxicity. However, the specific mechanism involved in heme mediated neurotoxicity has not been well studied.Methods In this study, we investigated the neurotoxicity of heme in neurons. Neurons were administrated with heme, and the cell death, autophagy and ER stress were analyzed. In addition, the relationship between autophagy and apoptosis in heme-induced cell death and the downstream effects were also detected.Results We showed that heme induced cell death and autophagy in neurons. The suppression of autophagy using either pharmacologic inhibitors (3-methyladenine) or RNA interference in essential autophagy genes (BECN1 and ATG5) decreased the cell death induced by heme in neurons. Moreover, ER stress activator thapsigargin increased the cell autophagy and cell death ratio following heme treatment. Autophagy promotes cell apoptosis and cell death induced by heme through BECN1/ ATG5 pathway.Conclusions Our findings suggest that heme potentiates neuron autophagy via ER stress, in turn inducing cell death via BECN1/ATG5 pathway. Targeting ER stress mediated autophagy might be a promising therapeutic strategy for ICH.