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Author Notes:

Kathy K. Griendling, Email: kgriend@emory.edu

MSH, LLH, JA, NG, YS, DK, and LC performed the experiments.

MSH and BL performed the statistical analysis.

KKG, BL, MY, CK, and MSH designed the experiments.

MSH and KKG wrote the manuscript.

All authors read and approved the final manuscript.

Confocal microscopy data for this study were acquired in the Microscopy in Medicine Core (MiM Core) at Emory University.

We thank Hong Yi and Jeannette Taylor of the Robert P. Apkarian Integrated Electron Microscopy Core at Emory University for the help with transmission electron microscopy.

We are also grateful to Dr. Nicholas Boulis in Neurosurgery for the use of his mouse RotaRod.

The authors declare that they have no competing interests.


Research Funding:

This work was supported by NIH grants HL038206 (to KKG), NS-079331 and NS-091201 (to MY), and FAPESP 24660-0 and AHA 17SDG33410777 grants (to MSH).


  • Science & Technology
  • Life Sciences & Biomedicine
  • Immunology
  • Neurosciences
  • Neurosciences & Neurology
  • Poldip2
  • Cerebral ischemia
  • Blood-brain barrier
  • Cytokines
  • Astrocytes

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

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Journal Title:

Journal of Neuroinflammation


Volume 15, Number 1


, Pages 45-45

Type of Work:

Article | Final Publisher PDF


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.

Copyright information:

© 2018 The Author(s).

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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