Endothelium-targeted overexpression of heat shock protein 27 ameliorates blood-brain barrier disruption after ischemic brain injury

Yejie Shi, Xiaoyan Jiang, Lili Zhang, Hongjian Pu, Xiaoming Hu, Wenting Zhang, Wei Cai, Yanqin Gao, Rehana K. Leak, Richard F. Keep, Michael V. L. Bennett, Jun Chen

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

The damage borne by the endothelial cells (ECs) forming the blood-brain barrier (BBB) during ischemic stroke and other neurological conditions disrupts the structure and function of the neurovascular unit and contributes to poor patient outcomes. We recently reported that structural aberrations in brain microvascular ECs - namely, uncontrolled actin polymerization and subsequent disassembly of junctional proteins, are a possible cause of the early onset BBB breach that arises within 30-60 min of reperfusion after transient focal ischemia. Here, we investigated the role of heat shock protein 27 (HSP27) as a direct inhibitor of actin polymerization and protectant against BBB disruption after ischemia/reperfusion (I/R). Using in vivo and in vitro models, we found that targeted overexpression of HSP27 specifically within ECs - but not within neurons - ameliorated BBB impairment 1-24 h after I/R. Mechanistically, HSP27 suppressed I/R-induced aberrant actin polymerization, stress fiber formation, and junctional protein translocation in brain microvascular ECs, independent of its protective actions against cell death. By preserving BBB integrity after I/R, EC-targeted HSP27 overexpression attenuated the infiltration of potentially destructive neutrophils and macrophages into brain parenchyma, thereby improving long-term stroke outcome. Notably, early poststroke administration of HSP27 attached to a cell-penetrating transduction domain (TAT-HSP27) rapidly elevated HSP27 levels in brain microvessels and ameliorated I/R-induced BBB disruption and subsequent neurological deficits. Thus, the present study demonstrates that HSP27 can function at the EC level to preserve BBB integrity after I/R brain injury. HSP27 may be a therapeutic agent for ischemic stroke and other neurological conditions involving BBB breakdown.

Original languageEnglish (US)
Pages (from-to)E1243-E1252
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number7
DOIs
StatePublished - Feb 14 2017

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HSP27 Heat-Shock Proteins
Blood-Brain Barrier
Brain Injuries
Endothelium
Endothelial Cells
Reperfusion
Ischemia
Polymerization
Actins
Stroke
Brain
Stress Fibers
Protein Transport
Microvessels
Reperfusion Injury
Neutrophils
Cell Death
Macrophages
Neurons

Keywords

  • Endothelial cell
  • HSP27
  • Neuroinflammation
  • Stress fiber
  • Tight junction

ASJC Scopus subject areas

  • General

Cite this

Endothelium-targeted overexpression of heat shock protein 27 ameliorates blood-brain barrier disruption after ischemic brain injury. / Shi, Yejie; Jiang, Xiaoyan; Zhang, Lili; Pu, Hongjian; Hu, Xiaoming; Zhang, Wenting; Cai, Wei; Gao, Yanqin; Leak, Rehana K.; Keep, Richard F.; Bennett, Michael V. L.; Chen, Jun.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, No. 7, 14.02.2017, p. E1243-E1252.

Research output: Contribution to journalArticle

Shi, Yejie ; Jiang, Xiaoyan ; Zhang, Lili ; Pu, Hongjian ; Hu, Xiaoming ; Zhang, Wenting ; Cai, Wei ; Gao, Yanqin ; Leak, Rehana K. ; Keep, Richard F. ; Bennett, Michael V. L. ; Chen, Jun. / Endothelium-targeted overexpression of heat shock protein 27 ameliorates blood-brain barrier disruption after ischemic brain injury. In: Proceedings of the National Academy of Sciences of the United States of America. 2017 ; Vol. 114, No. 7. pp. E1243-E1252.
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AU - Shi, Yejie

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AU - Pu, Hongjian

AU - Hu, Xiaoming

AU - Zhang, Wenting

AU - Cai, Wei

AU - Gao, Yanqin

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AU - Keep, Richard F.

AU - Bennett, Michael V. L.

AU - Chen, Jun

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AB - The damage borne by the endothelial cells (ECs) forming the blood-brain barrier (BBB) during ischemic stroke and other neurological conditions disrupts the structure and function of the neurovascular unit and contributes to poor patient outcomes. We recently reported that structural aberrations in brain microvascular ECs - namely, uncontrolled actin polymerization and subsequent disassembly of junctional proteins, are a possible cause of the early onset BBB breach that arises within 30-60 min of reperfusion after transient focal ischemia. Here, we investigated the role of heat shock protein 27 (HSP27) as a direct inhibitor of actin polymerization and protectant against BBB disruption after ischemia/reperfusion (I/R). Using in vivo and in vitro models, we found that targeted overexpression of HSP27 specifically within ECs - but not within neurons - ameliorated BBB impairment 1-24 h after I/R. Mechanistically, HSP27 suppressed I/R-induced aberrant actin polymerization, stress fiber formation, and junctional protein translocation in brain microvascular ECs, independent of its protective actions against cell death. By preserving BBB integrity after I/R, EC-targeted HSP27 overexpression attenuated the infiltration of potentially destructive neutrophils and macrophages into brain parenchyma, thereby improving long-term stroke outcome. Notably, early poststroke administration of HSP27 attached to a cell-penetrating transduction domain (TAT-HSP27) rapidly elevated HSP27 levels in brain microvessels and ameliorated I/R-induced BBB disruption and subsequent neurological deficits. Thus, the present study demonstrates that HSP27 can function at the EC level to preserve BBB integrity after I/R brain injury. HSP27 may be a therapeutic agent for ischemic stroke and other neurological conditions involving BBB breakdown.

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