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

DOI

10.1073/pnas.1621174114

Yejie Shi, State Key Laboratory of Medical Neurobiology, Institute of Brain Sciences and Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, China.
Xiaoyan Jiang, State Key Laboratory of Medical Neurobiology, Institute of Brain Sciences and Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, China.
Lili Zhang, Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA 15261.
Hongjian Pu, Pittsburgh Institute of Brain Disorders & Recovery and Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213.
Xiaoming Hu, State Key Laboratory of Medical Neurobiology, Institute of Brain Sciences and Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, China.
Wenting Zhang, State Key Laboratory of Medical Neurobiology, Institute of Brain Sciences and Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, China.
Wei Cai, Pittsburgh Institute of Brain Disorders & Recovery and Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213.
Yanqin Gao, State Key Laboratory of Medical Neurobiology, Institute of Brain Sciences and Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, China.
Rehana K. Leak, Division of Pharmaceutical Sciences, Mylan School of Pharmacy, Duquesne University, Pittsburgh, PA 15282.
Richard F. Keep, Department of Neurosurgery, University of Michigan, Ann Arbor, MI 48109.
Michael V. Bennett, State Key Laboratory of Medical Neurobiology, Institute of Brain Sciences and Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, China; michael.bennett@einstein.yu.edu chenj2@upmc.edu.
Jun Chen, State Key Laboratory of Medical Neurobiology, Institute of Brain Sciences and Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, China; michael.bennett@einstein.yu.edu chenj2@upmc.edu.

Document Type

Journal Article

Publication Date

2-14-2017

Publication Title

Proceedings of the National Academy of Sciences of the United States of America

Volume

114

Issue

7

First Page

E1243

Last Page

E1252

Keywords

HSP27, endothelial cell, neuroinflammation, stress fiber, tight junction

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.

Open Access

OA

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