| Title |
Polymerase delta-interacting protein 2 deficiency protects against blood-brain barrier permeability in the ischemic brain
|
|---|---|
| Published in |
Journal of Neuroinflammation, February 2018
|
| DOI | 10.1186/s12974-017-1032-1 |
| Pubmed ID | |
| 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 |
| Abstract |
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. 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. 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. 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. |
X Demographics
The data shown below were collected from the profiles of 3 X users who shared this research output. Click here to find out more about how the information was compiled.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Australia | 1 | 33% |
| United States | 1 | 33% |
| Unknown | 1 | 33% |
Demographic breakdown
| Type | Count | As % |
|---|---|---|
| Members of the public | 2 | 67% |
| Scientists | 1 | 33% |
Mendeley readers
The data shown below were compiled from readership statistics for 21 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Unknown | 21 | 100% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Student > Bachelor | 3 | 14% |
| Student > Ph. D. Student | 3 | 14% |
| Student > Master | 3 | 14% |
| Student > Postgraduate | 3 | 14% |
| Researcher | 1 | 5% |
| Other | 0 | 0% |
| Unknown | 8 | 38% |
| Readers by discipline | Count | As % |
|---|---|---|
| Neuroscience | 5 | 24% |
| Medicine and Dentistry | 4 | 19% |
| Agricultural and Biological Sciences | 1 | 5% |
| Biochemistry, Genetics and Molecular Biology | 1 | 5% |
| Unknown | 10 | 48% |
Attention Score in Context
This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 10 April 2019.
All research outputs
#15,492,327
of 23,023,224 outputs
Outputs from Journal of Neuroinflammation
#1,764
of 2,655 outputs
Outputs of similar age
#211,134
of 330,704 outputs
Outputs of similar age from Journal of Neuroinflammation
#44
of 76 outputs
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