A Dual Role of ATM in Ischemic Preconditioning and Ischemic Injury
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ORIGINAL RESEARCH
A Dual Role of ATM in Ischemic Preconditioning and Ischemic Injury Guang‑hui Xie1 · Han‑jun Dai2 · Fang Liu3 · Ying‑pei Zhang4 · Li Zhu5 · Jun‑jie Nie4 · Jian‑hua Wu4 Received: 27 July 2019 / Accepted: 5 December 2019 © Springer Science+Business Media, LLC, part of Springer Nature 2019
Abstract The ataxia-telangiectasia mutated (ATM) protein is regarded as the linchpin of cellular defenses to stress. Deletion of ATM results in strong oxidative stress and degenerative diseases in the nervous system. However, the role of ATM in neuronal ischemic preconditioning and lethal ischemic injury is still largely unknown. In this study, mice cortical neurons preconditioned with sublethal exposure to oxygen glucose deprivation (OGD) exhibited ATM/glucose-6-phosphate dehydrogenase pathway activation. Additionally, pharmacological inhibition of ATM prior to the preconditioning reversed neuroprotection provided by preconditioning in vitro and in vivo. Meanwhile, we found that ATM/P53 pro-apoptosis pathway was driven by lethal OGD injury, and pharmacological inhibition of ATM during fatal oxygen–glucose deprivation/reperfusion injury promoted neuronal survival. More importantly, inhibition of ATM activity after cerebral ischemia protected against cerebral ischemic-reperfusion damage in mice. In conclusion, our data show the dual role of ATM in neuronal ischemic preconditioning and lethal ischemic injury, involving in the protection of ischemic preconditioning, but promoting neuronal death in lethal ischemic injury. Thus, the present study provides new opportunity for the treatment of ischemic stroke. Keywords ATM · Ischemic brain injury · Preconditioning Abbreviations ATM Ataxia-telangiectasia mutated OGD Oxygen glucose deprivation DSBs Double-strand breaks HIF-1 Hypoxia-inducible factor 1 PC Preconditioning NADPH Nicotinamide adenine dinucleotide phosphate GSH Glutathione MCAO Middle cerebral artery occlusion Guang-hui Xie and Han-jun Dai have contributed equally to this work. * Jian‑hua Wu [email protected] 1
Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
2
Department of Ophthalmology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
3
General surgery department of Xinhua Hospital of Hubei Province, Wuhan 430015, China
4
Department of Pharmacy, Zhongnan Hospital of Wuhan University, Dong‑Hu Road #169, Wuhan 430071, Hubei, China
5
Department of Pharmacy, Tongren Hospital of Wuhan University, Wuhan 430071, China
HDAC4 Histone deacetylase 4 CREB CAMP-response element binding protein TTC 2,3,5-Triphenyltetrazolium chloride TUNEL Terminal deoxynucleotidyl transferase (TdT)mediated dUTP nick end labeling G6PD Glucose-6-phosphate dehydrogenase γ-H2AX Phosphorylated Histone H2AX
Introduction Ischemic stroke, also known as brain ischemia, is a major type of stroke and is usually caused by insufficiency of oxygen and glucose supply due to a localized blood supply disorder induced by cerebral artery embolism (Wu et al. 2012). It is the
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