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Epigenetic Regulation of Ferroportin in Primary Cultures of the Rat Blood-Brain Barrier

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Abstract

Ferroportin plays an essential role for iron transport through the blood-brain barrier (BBB), which is formed by brain capillary endothelial cells (BCECs). To maintain the integrity of the BBB, the BCECs gain support from pericytes and astrocytes, which together with neurons form the neurovascular unit (NVU). The objectives of the present study were to investigate ferroportin expression in primary cells of the NVU and to determine if ferroportin mRNA (Fpn) expression is epigenetically regulated. Primary rat BCECs, pericytes, astrocytes, and neurons all expressed ferroportin mRNA at varying levels, with BCECs exhibiting the highest expression of Fpn, peaking when co-cultured but examined separately from astrocytes. Conversely, Fpn expression was lowest in isolated astrocytes, which correlated with high DNA methylation in their Slc40a1 promoter. To provide further evidence for epigenetic regulation, mono-cultured BCECs, pericytes, and astrocytes were treated with the histone deacetylase inhibitors valproic acid (VPA) and sodium butyrate (SB), which significantly increased Fpn and ferroportin protein in BCECs and pericytes. Furthermore, 59Fe export from BCECs was elevated after treatment with VPA. In conclusion, we present first time evidence stating that Fpn expression is epigenetically regulated in BCECs, which may have implications for pharmacological induction of iron transport through the BBB.

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Abbreviations

5mC:

5-Methylcytosine

α-SMA:

α-Smooth actin

Actb:

β-Actin

ARE:

Antioxidant responsive element

BACH1:

BTB and CNC homology 1

BBB:

Blood-brain barrier

BCECs:

Brain capillary endothelial cells

BSA:

Bovine serum albumin

cDNA:

Complementary DNA

CG:

Cytosine-guanine

DAPI:

4′,6-diamidino-2-phenylindole

DMEM:

Dulbecco’s modified Eagle’s medium

DMSO:

Dimethyl sulfoxide

DMT1:

Divalent metal transporter 1

EDTA:

Ethylenediaminetetraacetic acid

ELISA:

Enzyme-linked immunosorbent assay

FCS:

Fetal calf serum

Fe:

Iron

Fpn:

Ferroportin

GFAP:

Glial fibrillary acidic protein

HDAC:

Histone deacetylase

HDACi:

Histone deacetylase inhibitor

IRE:

Iron responsive element

IRP:

Iron regulatory protein

NRF2:

Nuclear factor (erythroid-derived 2)-like-2

NVU:

Neurovascular unit

PBS:

Phosphate-buffered saline

SAM:

S­Adenosylmethionine

SB:

Sodium butyrate

TfR1:

Transferrin receptor 1

VPA:

Valproic acid

TEER:

Trans-endothelial electrical resistance

TSS:

Transcription start site

TU-20:

β3 tubulin

ZO-1:

Zonula occludens protein 1

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Acknowledgments

We thank Merete Fredsgaard and Hanne Krone Nielsen, Aalborg University, Denmark, for their excellent technical assistance. We also thank Lykke Christina Grubach, Clinical Diagnostics Department at Aalborg University Hospital, Denmark for providing technical instruments.

Funding

The present work has been supported by the Danish Multiple Sclerosis Society, “Kong Christian den Tiendes fond,” “Åse og Ejner Danielsens Fond,” and the Lundbeck Foundation Research Initiative on Brain Barriers and Drug Delivery (Grant no. R155-2013-14113).

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Authors and Affiliations

  1. Neurobiology Research and Drug Delivery (NRD) Department of Health Science and Technology, Aalborg University, Fr. Bajers Vej 3B, 9220, Aalborg, Denmark

    Steinunn Sara Helgudottir, Lisa J. Routhe, Annette Burkhart & Torben Moos

  2. Department of Health Technology, Center for Nanomedicine and Theranostics, Technical University of Denmark, Copenhagen, Denmark

    Katrine Jønsson

  3. Department of Clinical Medicine, Aalborg University Hospital, Aalborg, Denmark

    Inge S. Pedersen

  4. Department of Molecular Diagnostics, Aalborg University Hospital, Aalborg, Denmark

    Inge S. Pedersen

  5. Laboratory of Molecular Pharmacology, Department of Health Science and Technology, Aalborg University, Fr. Bajers Vej 7E, 9220, Aalborg, Denmark

    Jacek Lichota

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  1. Steinunn Sara Helgudottir
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Helgudottir, S.S., Routhe, L.J., Burkhart, A. et al. Epigenetic Regulation of Ferroportin in Primary Cultures of the Rat Blood-Brain Barrier. Mol Neurobiol 57, 3526–3539 (2020). https://doi.org/10.1007/s12035-020-01953-y

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