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Aberrantly expressed long noncoding RNAs are involved in sevoflurane-induced developing hippocampal neuronal apoptosis: a microarray related study

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Abstract

The commonly used volatile anesthetic sevoflurane has been shown to induce widespread apoptosis in the developing brain, yet the underlying molecular mechanisms are not fully understood. Accumulating research has demonstrated that long noncoding RNAs (lncRNAs) regulate multiple biological processes, including neural development, differentiation and apoptosis. They are aberrantly expressed in multiple neurodegenerative diseases. In this study, we employed a lncRNA-mRNA microarray analysis to determine whether and how lncRNAs are involved in sevoflurane-induced hippocampal neuronal apoptosis in neonatal mice. Our data showed that a single 6-h sevoflurane exposure of P7 mice resulted in significant morphological changes and apoptosis in the hippocampus. Moreover, the microarray simultaneously revealed 817 lncRNAs and 856 of their potential coding targets that related to apoptosis, of which 31 lncRNAs (19 up and 12 down) and 25 mRNAs were significantly differentially expressed (P < 0.05) after sevoflurane exposure. Importantly, we found that Bcl2l11 (BIM), which potentiates mitochondria-dependent apoptosis and its nearby enhancer-like lncRNA ENSMUST00000136025, were both more highly expressed in sevoflurane-treated samples compared with control samples. Subsequent qRT-PCR results confirmed the changes. Further CNC network indicated that lncRNA ENSMUST00000136025 was positively correlated with Bim. Moreover, sevoflurane induced a significant increase of pro-apoptotic protein BIM and Bax but a reduction of anti-apoptotic proteins Bcl-2 in the hippocampus. Our study first demonstrates that aberrantly expressed lncRNAs play a role in sevoflurane-induced hippocampal apoptosis. We noted that up-regulated ENSMUST00000136025 highly likely induced the over-expression of BIM, which eventually promoted mitochondria-mediated apoptosis. Such findings further broaden the understanding of molecular mechanisms responsible for sevoflurane-induced neurotoxicity.

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Acknowledgments

This work was supported by National Natural Science Foundation of China (grant NO. 81571032) and Guangdong Science and Technology Planning Project (grant no. 2013B051000045).

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Authors and Affiliations

  1. Department of Anesthesiology, Fujian Provincial Hospital, Fujian Provincial Clinical Medical College, Fujian Medical University, Fuzhou, 350001, China

    Xiaohui Chen & Yanqing Chen

  2. Department of Anesthesiology, The First Affiliated Hospital of Sun Yat-Sen University, No 58 zhongshan Road 2, Guangzhou, 510080, China

    Xiaohui Chen, Xue Zhou, Dihan Lu, Xiaoyu Yang, Zhibin Zhou, Xi Chen & Xia Feng

  3. Department of Cardiology, The First Affiliated Hospital of Sun Yat-Sen University, No 58 zhongshan Road 2, Guangzhou, 510080, China

    Wen He

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  1. Xiaohui Chen
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Correspondence to Xia Feng.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of Institutional Animal Care and Use Committee at Sun Yat-Sen University (Guangzhou, Guangdong, China).

This article does not contain any studies with human participants performed by any of the authors.

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There is no conflict of interests regarding the publication of this paper.

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Xiaohui Chen and Xue Zhou contributed equally to this work.

Electronic Supplementary Material

Supplementary Fig. 1

CNC network of the ten most significantly changed lncRNAs. The network represents co-expression correlations between the ten significantly differentially expressed lncRNAs and mRNAs. Orange rectangle nodes represent the ten most significantly changed lncRNAs in the network, while the light-blue round nodes represent hundreds of co-expressed mRNAs, and red nodes were related to several known bcl2 family. Correlation degrees for each pair of nodes were measured and delineated by the length of the lines. (GIF 163 kb)

High Resolution Image (TIFF 192132 kb)

Supplementary Table 1

Differentially expressed lncRNAs in microarray analysis (XLS). The table present the lncRNAs differentially expressed with an absolute fold-change >1.5. (XLS 54 kb)

Supplementary Table 2

Differentially Expressed mRNAs in microarray analysis (XLS). The table present the mRNAs differentially expressed with an absolute fold-change >1.5. (XLS 31 kb)

Supplementary Table 3

Predicted regulation for lncRNAs and their potential target genes in microarray analysis (XLS). The lncPath™ arrays profile lncRNAs and their target genes simultaneously in a pathway-focused manner. Three types of LncRNAs are included in LncPath™ arrays: enhancer-like LncRNAs、ceRNAs、neighboring LncRNAs. (XLS 792 kb)

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Chen, X., Zhou, X., Lu, D. et al. Aberrantly expressed long noncoding RNAs are involved in sevoflurane-induced developing hippocampal neuronal apoptosis: a microarray related study. Metab Brain Dis 31, 1031–1040 (2016). https://doi.org/10.1007/s11011-016-9838-6

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  • DOI: https://doi.org/10.1007/s11011-016-9838-6

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