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P2X7 Receptors Mediate CO-Induced Alterations in Gene Expression in Cultured Cortical Astrocytes—Transcriptomic Study

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Abstract

Carbon monoxide (CO) is an endogenous gasotransmitter that limits inflammation and prevents apoptosis in several tissues, including the brain. Low concentrations of CO are cytoprotective in astrocytes, neurons, and microglia, but the underlying molecular mechanisms remain poorly understood. This work aims at identification of alterations in gene expression conferred by CO in primary cultures of cortical astrocytes, for further disclosure of the molecular mechanism of action of the gasotransmitter. Astrocytes were treated with the CO-releasing molecule CORM-A1 for 40 min, and transcriptional changes were analyzed using RNASeq. A total of 162 genes were differentially expressed in response to CO treatment, and 7 of these genes were selected for further analysis: FosB, Scand1, Rgs10, Actg1, Panx1, Pcbdh21, and Rn18s. The alterations in their expression were further validated using qRT-PCR. An increase in FosB protein expression was also observed after 40 min of CORM-A1 treatment, as determined by a western blot. CO-induced FosB expression and cytoprotection were both abrogated in the presence of the P2X7 receptor antagonist A-438079. Furthermore, CORM-A1 increased phosphorylation of calcium/calmodulin-dependent protein kinase II (CaMKII), which is a downstream event of P2X7R activation. The functional importance of FosB in CO-induced survival was assessed by knocking down its expression with FosB siRNA. Astrocytes were challenged to death with oxidative stress and cell viability was assessed 24 h later. Downregulation of FosB did not prevent the effects of CO in the inhibition of astrocytic cell death. Nevertheless, the transcriptomic changes observed upon treatment of astrocytes with CO open new opportunities for further studies on CO cytoprotective pathways.

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Abbreviations

Actg1:

Actin gamma 1

AP-1:

Activator protein 1

ATF:

Activating transcription factor

Bcl-2:

B cell leukemia/lymphoma 2

BDNF:

Brain-derived neurotrophic factor

CBP:

CREB binding protein

CaMKII:

Ca2+/calmodulin-dependent protein kinase II

CO:

Carbon monoxide

CORM-A1:

Carbon monoxide-releasing molecule A1

CREB:

cAMP-response element-binding protein

DEGs:

Differentially expressed genes

ERK:

Extracellular signal-regulated kinase

FRK:

Fos-regulating kinase

Gapdh:

Glyceraldehyde-3-phosphate dehydrogenase

HO-1:

Haem oxygenase-1

Hprt1:

Hypoxanthine guanine phosphoribosyl transferase I

JAK:

Janus kinase

JNK:

c-Jun N-terminal kinase

MAPK:

Mitogen-activated protein kinase

MMP:

Mitochondria membrane potential

NAC:

N-acetylcysteine

Ppia:

Peptidylprolyl isomerase A

PPARɣ:

Peroxisome proliferator-activated receptor gamma

PI:

Propidium iodide

P2X7R:

P2X7 receptor

qRT-PCR:

Quantitative real-time reverse transcription-polymerase chain reaction

Rn18s:

18S rRNA

Sdha:

Succinate dehydrogenase complex, subunit A

sGC:

Soluble guanylyl cyclase

siRNA:

Small interfering RNA

SRE:

Serum response element

t-BHP:

tert-Butyl hydroperoxide

TCF:

Ternary complex factor

TRE:

12-O-Tetradecanoylphorbol-13-acetate (TPA) response element (consensus sequence 5′-TGAG/CTCA-3′)

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Acknowledgements

We thank Pedro Fernandes for his support and expertise on RNAseq data analysis and Miranda Mele for helping in RNA processing and analysis. SRO was supported by a fellowship from Fundação para a Ciência e a Tecnologia (FCT) with reference SFRH/BD/51969/2012 and CFP’s fct supported by a fellowship with reference PD/BD/106057/2015. HLAV’s FCT support IF/00185/2012.

Funding

This work was supported by FEDER (QREN) through Programa Mais Centro, under projects CENTRO-07-ST24-FEDER-002002, CENTRO-07-ST24-FEDER-002006 and CENTRO-07-ST24-FEDER-002008, through Programa Operacional Factores de Competitividade—COMPETE 2020 and National funds via FCT—Fundação para a Ciência e a Tecnologia under projects COMPETE: POCI-01-0145-FEDER-007440, Pest-C/SAU/LA0001/2013-2014, PTDC/SAU-NMC/120144/2010, PTDC/NEU-NMC/0198/2012 and FCT-ANR/NEU-NMC/0022/2012.

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Authors and Affiliations

  1. CNC- Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal

    Sara R. Oliveira & Carlos B. Duarte

  2. CEDOC, Chronic Diseases Research Centre, NOVA Medical School/Faculdade de Ciência Médicas, Universidade Nova de Lisboa, 1169-056, Lisbon, Portugal

    Sara R. Oliveira, Cláudia Figueiredo-Pereira & Helena L. A. Vieira

  3. Institute for Interdisciplinary Research (IIIUC), University of Coimbra, Coimbra, Portugal

    Sara R. Oliveira

  4. Department of Life Sciences, University of Coimbra, Coimbra, Portugal

    Carlos B. Duarte

  5. Instituto de Biologia Experimental e Tecnológica (iBET), Apartado 12, 2781-901, Oeiras, Portugal

    Helena L. A. Vieira

Authors
  1. Sara R. Oliveira
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  2. Cláudia Figueiredo-Pereira
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  3. Carlos B. Duarte
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  4. Helena L. A. Vieira
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Contributions

SRO performed experimental procedures and carried out the analysis and interpretation of data. CFP performed experimental procedures. HLAV and CBD participated in the discussion of data and critically reviewed the manuscript. SRO, HLAV, and CBD participated in the conception and design of the study, as well as in the analysis and interpretation of data. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Helena L. A. Vieira.

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Oliveira, S.R., Figueiredo-Pereira, C., Duarte, C.B. et al. P2X7 Receptors Mediate CO-Induced Alterations in Gene Expression in Cultured Cortical Astrocytes—Transcriptomic Study. Mol Neurobiol 56, 3159–3174 (2019). https://doi.org/10.1007/s12035-018-1302-7

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