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Ischemic Postconditioning Confers Cerebroprotection by Stabilizing Yao et al. Cell Death and Disease (2018) 9:1033 DOI 10.1038/s41419-018-1089-5 Cell Death & Disease ARTICLE Open Access Ischemic postconditioning confers cerebroprotection by stabilizing VDACs after brain ischemia Gui-Ying Yao1,2, Qian Zhu1,2, Jing Xia1,2, Feng-Jiao Chen1,2,MingHuang1,2, Jing Liu1,2, Ting-Ting Zhou1,2, Jian-Feng Wei1,3, Gui-Yun Cui1,4, Kui-Yang Zheng3 and Xiao-Yu Hou1,2 Abstract Ischemic postconditioning provides robust neuroprotection, therefore, determining the molecular events may provide promising targets for stroke treatment. Here, we showed that the expression of functional mitochondrial voltage- dependent anion channel proteins (VDAC1, VDAC2, and VDAC3) reduced in rat vulnerable hippocampal CA1 subfield after global ischemia. Ischemic postconditioning restored VDACs to physiological levels. Stabilized VDACs contributed to the benefits of postconditioning. VDAC1 was required for maintaining neuronal Ca2+ buffering capacity. We found that microRNA-7 (miR-7) was responsible for postischemic decline of VDAC1 and VDAC3. Notably, miR-7 was more highly expressed in the peripheral blood of patients with acute ischemic stroke compared to healthy controls. Inhibition of miR-7 attenuated neuronal loss and ATP decline after global ischemia, but also diminished the infarct volume with improved neurological functions after focal ischemia. Thus, ischemic postconditioning protects against mitochondrial damage by stabilizing VDACs. MiR-7 may be a potential therapeutic target for ischemic stroke. 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; – Introduction delayed neuronal loss after brain ischemia5 9. Thus far, Stroke is one of the leading causes of adult disability and the molecular mechanisms underlying the endogenous mortality worldwide1. Acute ischemic stroke (AIS), neuroprotective effects remain to be defined. caused by systemic hypoperfusion, in situ thrombosis, or Mitochondria are associated with multiple cellular embolism, is the most prevalent form of cerebrovascular processes including cell metabolism and cell survival, disease. Early reperfusion, the only widely approved which implicate mitochondria as having endogenous clinical treatment, causes an additional delayed damage neuroprotective functions. Voltage-dependent anion – to the ischemic brain2 4. Much attention has been channels (VDACs) are the most abundant proteins in focused on developing novel neuroprotective strategies the outer mitochondrial membranes (OMM)10. The three for administration after brain ischemia. Ischemic post- VDAC isoforms (VDAC1, VDAC2, and VDAC3) are conditioning, a single or a series of brief interference (s) present and share a high structural homology in mam- in the cerebral blood supply performed after a prolonged mals11,12. VDACs, together with the adenine nucleotide severe brain ischemia, has been shown to protect against translocator 1 (ANT1) in the inner mitochondrial mem- brane (IMM), function as efficient exchange channels for ATP/ADP. Moreover, VDACs modulate the movement Correspondence: X-Y. Hou ([email protected]) 1 of other small metabolites such as citrate and pyruvate Jiangsu Key Laboratory of Brain Disease Bioinformation, Xuzhou Medical 13 University, Xuzhou, Jiangsu, China into and out of the mitochondrion and cytoplasm . 2Research Center for Biochemistry and Molecular Biology, Xuzhou Medical VDACs have been reported to regulate cancer cell sur- University, Xuzhou, Jiangsu, China vival by interacting with anchored proteins such as Full list of author information is available at the end of the article. These authors contributed equally: Gui-Ying Yao, Qian Zhu. Edited by: B. Joseph. © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a linktotheCreativeCommons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Official journal of the Cell Death Differentiation Association Yao et al. Cell Death and Disease (2018) 9:1033 Page 2 of 15 – hexokinase 1 (HK1)14,15 and Bcl-2 family members16 19. Stabilized VDAC expression is responsible for the Although VDAC1 overexpression has also been impli- postconditioning-induced neuroprotection – cated in neurodegenerative diseases20 22, it is unknown Next, we determined the contribution of VDAC1, about the contributions of VDACs to ischemic brain the most studied VDAC isoform in rat brain mito- damage and underlying molecular mechanisms. chondria, to the postconditioning-induced benefits In the present study, we examined the expression of using siRNA-mediated knockdown. The efficiency VDACs in the rat brain after global and focal ischemia. and specificity of VDAC1 siRNA (si-VDAC1) were We determined whether and how VDAC1, an abundant confirmed by immunoblot in rat hippocampus (Fig. 3a). isoform of VDACs is involved in the prosurvival respon- Nissl staining was performed 5 days after I/R to ses triggered by ischemic postconditioning23. We also measure the surviving neurons. As shown in Fig. 3b, investigated the molecular mechanisms regulating VDAC the ischemic postconditioning group had greater survi- expression, which could provide a potential biomarker val of hippocampal CA1 pyramidal neurons compared and therapeutic target for AIS. with those of the I/R group. Conversely, si-VDAC1 delivery abolished the beneficial effect of ischemic Results postconditioning and triggered severe CA1 pyramidal Ischemic postconditioning prevents VDAC loss in the rat neuronal loss similar to the I/R group, whereas the hippocampal CA1 subfield negative control sequence of siRNA (si-NC) did not Multiple reciprocal mechanisms are associated with alter neuronal survival (Fig. 3b). These findings confirm neuronal susceptibility to ischemia followed by reper- that stabilized levels of VDAC1 are required for fusion, including excitotoxicity, mitochondrial failure, neuronal survival mediated by postconditioning. oxidative stress, nitrative stress, and inflammation24,25. Moreover, si-VDAC2 and si-VDAC3 attenuated the Previously, we confirmed the efficacy of brief single postconditioning-induced neuroprotection (Supple- postconditioning ischemia in a global ischemic model mentaryFigureS2),suggestingthatstablepresenceof andprovidedevidencethatischemic postconditioning VDAC2 and VDAC3 also play important roles in neu- prevents excitotoxic signaling8. To further determine ronal survival after ischemic stroke. whether ischemic postconditioning confers mitochon- drial protection, we measured the expression of the Stabilized VDAC1 is required for intracellular calcium mitochondrial functional VDACs after global ischemia homeostasis 2+ 2+ with or without postconditioning. As shown in Fig. 1a, The overload of intracellular Ca ([Ca ]i) is a major remarkable decreases in all three VDAC isoforms, cause of delayed neuronal death after brain ischemia28,29. especially VDAC1 and VDAC3, were observed in rat To measure the responses associated with VDAC1 defi- vulnerable hippocampal CA1 subfield after 15 min of ciency after brain ischemia, an efficient ionophore, iono- 2+ global ischemia followed by reperfusion (I/R). In con- mycin, was used to elevate the levels of [Ca ]i in HT22 + trast, I/R did not alter the expression of OMM protein mouse hippocampal cells. Ionomycin elicits a Ca2 influx mitofusin 1 in the CA1 subfield (Supplementary Fig- across the plasma membrane by stimulating store- ure S1). Ischemic postconditioning restored all VDAC regulated cation entry30. Depletion of VDAC1 had no 2+ +/− expressions to the basal levels (Fig. 1a). The expression effect upon resting [Ca ]i in VDAC1 HT22 cells + + levels of three VDAC isoforms were not affected in comparing with VDAC1 / cells (Fig. 4a, b). Ionomycin 2+ relatively resistant hippocampal CA3/DG subfields after (2 μM) treatment induced a dramatic elevation of [Ca ]i + + + − I/R (Fig. 1b). The stable expression of cytochrome within 1 min in both VDAC1 / and VDAC1 / HT22 2+ c oxidase subunit 4 (COX4) and unaltered mtDNA copy cells. The [Ca ]i declined 10 min after ionomycin + + number precluded the possibility of mitochondrial administration in VDAC1 / HT22 cells (Fig. 4c, d). number reduction at the early stage of reperfusion in the Under the condition of intracellular calcium overload, no CA1 subfield (Fig. 1a–c), which is consistent with pre- difference was found in intramitochondrial calcium + + + − vious study26,27. Quantitative real-time PCR (qReal-time between VDAC1 / and VDAC1 / HT22 cells (Fig. 4e). 2+ PCR) analyses showed that mRNA levels of VDACs Caffeine increases [Ca ]i level by calcium-induced decreased in CA1 region after ischemia (Fig. 2a), while calcium release through ryanodine receptors in endo- it was restored to basal levels following ischemic post- plasmic reticula31. Application of caffeine (20 mM)-eli- conditioning treatment (Fig. 2b). cited calcium responses showed a similar tendency with + + + − These data suggest that
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