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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2018

Open Access 01-12-2018 | Research

Polymerase delta-interacting protein 2 deficiency protects against blood-brain barrier permeability in the ischemic brain

Authors: Marina S. Hernandes, Bernard Lassègue, Lula L. Hilenski, Jonathan Adams, Ning Gao, Chia-Yi Kuan, Yu-Yo Sun, Lihong Cheng, Daniel S. Kikuchi, Manuel Yepes, Kathy K. Griendling

Published in: Journal of Neuroinflammation | Issue 1/2018

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Abstract

Background

Polymerase δ-interacting protein 2 (Poldip2) is a multifunctional protein that regulates vascular extracellular matrix composition and matrix metalloproteinase (MMP) activity. The blood-brain barrier (BBB) is a dynamic system assembled by endothelial cells, basal lamina, and perivascular astrocytes, raising the possibility that Poldip2 may be involved in maintaining its structure. We investigated the role of Poldip2 in the late BBB permeability induced by cerebral ischemia.

Methods

Transient middle cerebral artery occlusion (tMCAO) was induced in Poldip2+/+ and Poldip2+/− mice. The volume of the ischemic lesion was measured in triphenyltetrazolium chloride-stained sections. BBB breakdown was evaluated by Evans blue dye extravasation. Poldip2 protein expression was evaluated by western blotting. RT-PCR, zymography, and ELISAs were used to measure mRNA levels, activity, and protein levels of cytokines and MMPs. Cultured astrocytes were transfected with Poldip2 siRNA, and mRNA levels of cytokines were evaluated as well as IκBα protein degradation.

Results

Cerebral ischemia induced the expression of Poldip2. Compared to Poldip2+/+ mice, Poldip2+/− animals exhibited decreased Evans blue dye extravasation and improved survival 24 h following stroke. Poldip2 expression was upregulated in astrocytes exposed to oxygen and glucose deprivation (OGD) and siRNA-mediated downregulation of Poldip2 abrogated OGD-induced IL-6 and TNF-α expression. In addition, siRNA against Poldip2 inhibited TNF-α-induced IκBα degradation. TNF-α, IL-6, MCP-1, VEGF, and MMP expression induced by cerebral ischemia was abrogated in Poldip2+/− mice. The protective effect of Poldip2 depletion on the increased permeability of the BBB was partially reversed by systemic administration of TNF-α.

Conclusions

Poldip2 is upregulated following ischemic stroke and mediates the breakdown of the BBB by increasing cerebral cytokine production and MMP activation. Therefore, Poldip2 appears to be a promising novel target for the development of therapeutic strategies to prevent the development of cerebral edema in the ischemic brain.
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Metadata
Title
Polymerase delta-interacting protein 2 deficiency protects against blood-brain barrier permeability in the ischemic brain
Authors
Marina S. Hernandes
Bernard Lassègue
Lula L. Hilenski
Jonathan Adams
Ning Gao
Chia-Yi Kuan
Yu-Yo Sun
Lihong Cheng
Daniel S. Kikuchi
Manuel Yepes
Kathy K. Griendling
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2018
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-017-1032-1

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