Heme Induces BECN1/ATG5-Mediated Autophagic Cell Death via ER Stress in Neurons
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ORIGINAL ARTICLE
Heme Induces BECN1/ATG5-Mediated Autophagic Cell Death via ER Stress in Neurons Zhao Yang 1 & Changlong Zhou 1 & Hui Shi 1 & Nan Zhang 2 & Bin Tang 3 & Na Ji 4 Received: 2 April 2020 / Revised: 11 July 2020 / Accepted: 19 August 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Intracerebral hemorrhage (ICH) is a serious medical problem, and effective treatment is limited. Hemorrhaged blood is highly toxic to the brain, and heme, which is mainly released from hemoglobin, plays a vital role in neurotoxicity. However, the specific mechanism involved in heme-mediated neurotoxicity has not been well studied. In this study, we investigated the neurotoxicity of heme in neurons. Neurons were treated with heme, and cell death, autophagy, and endoplasmic reticulum (ER) stress were analyzed. In addition, the relationship between autophagy and apoptosis in heme-induced cell death and the downstream effects were also assessed. We showed that heme induced cell death and autophagy in neurons. The suppression of autophagy using either pharmacological inhibitors (3-methyladenine) or RNA interference of essential autophagy genes (BECN1 and ATG5) decreased heme-induced cell death in neurons. Moreover, the ER stress activator thapsigargin increased cell autophagy and the cell death ratio following heme treatment. Autophagy promoted heme-induced cell apoptosis and cell death through the BECN1/ ATG5 pathway. Our findings suggest that heme potentiates neuronal autophagy via ER stress, which in turn induces cell death via the BECN1/ATG5 pathway. Targeting ER stress-mediated autophagy might be a promising therapeutic strategy for ICH. Keywords Heme . Autophagic death . ER stress . Neuron
Introduction Intracerebral hemorrhage (ICH) accounts for 10–15% of all strokes and causes severe disability and mortality (Khatri et al. 2019; Sennfalt et al. 2018; Yu et al. 2019). During ICH, large numbers of erythrocytes are released into the extracellular spaces in the brain. After these erythrocytes are lysed, extracellular hemoglobin is rapidly oxidized into methemoglobin
* Bin Tang [email protected] * Na Ji [email protected] 1
Department of Neurology and Chongqing Key Laboratory of Cerebrovascular Disease, Yongchuan Hospital, Chongqing Medical University, Chongqing 402160, China
2
Department of Urology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
3
Department of General Surgery, The Third Affiliated Hospital of Chongqing Medical University, Chongqing 401120, China
4
Department of Anesthesia, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
and releases heme (Chen-Roetling et al. 2012; Takeuchi et al. 2013). Free heme binds to lipids, intercalating into cell membranes and leading to neuron damage (Caliaperumal et al. 2013; Lakovic et al. 2014; Shen et al. 2015). Autophagy is a fundamental biological process that endows eukaryotic cells with the ability to autodigest portions of their own cy
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