Autophagy activation aggravates hippocampal neuronal apoptosis caused by intermittent hypoxia

Jin Tan,Mengmeng Li,Qiang Zhang,Lulu Li,Cong Wang,Yuyang Miao,Xiaofei Meng,Shuling Song,Yunyun Fang

doi:10.18632/oncotarget.23845

Abstract

// Jin Tan 1, * , Mengmeng Li 1, * , Xiaofei Meng 1, * , Shuling Song 1, * , Yunyun Fang 1 , Lulu Li 1 , Cong Wang 1 , Yuyang Miao 2 and Qiang Zhang 1 1 Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin Geriatrics Institute, Tianjin, China 2 Tianjin Medical University, Tianjin, China * These authors contributed equally to this work Correspondence to: Qiang Zhang, email: zhangqiangyulv@163.com Keywords: intermittent hypoxia; autophagy; apoptosis; hippocampal neuron; HIF-1α Received: September 19, 2017 Accepted: December 04, 2017 Published: January 02, 2018 ABSTRACT Unlike the role of autophagy in continuous hypoxia, the role of autophagy in intermittent hypoxia is unclear. To investigate whether autophagy is involved in intermittent hypoxia- caused hippocampal neuronal apoptosis, we studied the activity and action of autophagy in hippocampal neurons after exposure to intermittent hypoxia. We found the expression of autophagy-related proteins and the autolysosome formation were upregulated, and exposure to intermittent hypoxia led to a significant increase in light chain 3 (LC3) turnover and a decrease in SQSTM1/p62 level in hippocampal neurons. Furthermore, accompanying autophagy activation, the level of hypoxia inducible factor-1α (HIF-1α) was increased. Conversely, inhibition of HIF-1α by chemical inhibitor or small interfering RNA (siRNA) downregulated the expression of autophagy-related proteins and blocked autophagy activation. We also found reactive oxygen species (ROS) increased after exposure to intermittent hypoxia, and inhibition of ROS by antioxidants decreased LC3-II expression. What’s more, activation of autophagy by rapamycin exacerbated the apoptosis induced by intermittent hypoxia, whereas inhibition of autophagy by chloroquine or autophagy-related genes siRNA ( Beclin1, Atg5 and Atg7 ) ameliorated intermittent hypoxia-induced apoptosis. Additionally, X-linked inhibitor of apoptosis protein (XIAP), an apoptosis inhibitor protein, was decreased significantly after autophagy activation. Taken together, HIF-1α and ROS-mediated autophagy activation aggravated hippocampal neuronal apoptosis caused by intermittent hypoxia, and the decrease of XIAP might be one of the mechanisms of hippocampal neuronal apoptosis caused by autophagy activation.

Highlights

Autophagy is a cellular process that engulfs, digests, and recycles long-lived or aggregated proteins, defective organelles, and various soluble molecules to sustain cellular metabolism [1]
We found that the expression of autophagy marker proteins light chain 3 (LC3)-II and Beclin1 in hippocampal neurons were increased after intermittent hypoxia treatment
These results suggest that autophagy may be induced by intermittent hypoxia in hippocampal neurons

Summary

Introduction

Autophagy is a cellular process that engulfs, digests, and recycles long-lived or aggregated proteins, defective organelles, and various soluble molecules to sustain cellular metabolism [1]. Previous studies have shown that autophagy is activated in many neuronal diseases such as cerebral hemorrhage, cerebral ischemia, Alzheimer’s disease and Parkinson’s disease. Stimulation of autophagy during cerebral hemorrhage is a cell-defense mechanism [2], while excessive activation of autophagy in ischemiareperfusion injury which occurs during cerebral ischemia can aggravate cellular injury [5]. In chronic and moderate continuous hypoxia, autophagy plays a protective role by removal of damaged organelles and proteins. Contrary to the protective role of autophagy, during rapid and severe oxygen fluctuations, autophagy may be detrimental and induce cell death [6]. This new evidence suggests the www.impactjournals.com/oncotarget s55

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