title: HSP27 protects the blood-brain barrier against ischemia-induced loss of integrity.
abstract: Loss of integrity of the blood-brain barrier (BBB) in stroke victims initiates a devastating cascade of events including extravasation of blood-borne molecules, water, and inflammatory cells deep into brain parenchyma. Thus, it is important to identify mechanisms by which BBB integrity can be maintained in the face of ischemic injury in experimental stroke. We previously demonstrated that the phylogenetically conserved small heat shock protein 27 (HSP27) protects against transient middle cerebral artery occlusion (tMCAO). Here we show that HSP27 transgenic overexpression also maintains the integrity of the BBB in mice subjected to tMCAO. Extravasation of endogenous IgG antibodies and exogenous FITC-albumin into the brain following tMCAO was reduced in transgenic mice, as was total brain water content. HSP27 overexpression abolished the appearance of TUNEL-positive profiles in microvessel walls. Transgenics also exhibited less loss of microvessel proteins following tMCAO. Notably, primary endothelial cell cultures were rescued from oxygen-glucose deprivation (OGD) by lentiviral HSP27 overexpression according to four viability assays, supporting a direct effect on this cell type. Finally, HSP27 overexpression reduced the appearance of neutrophils in the brain and inhibited the secretion of five cytokines. These findings reveal a novel role for HSP27 in attenuating ischemia/reperfusion injury - the maintenance of BBB integrity. Endogenous upregulation of HSP27 after ischemia in wild-type animals may exert similar protective functions and warrants further investigation. Exogenous enhancement of HSP27 by rational drug design may lead to future therapies against a host of injuries, including but not limited to a harmful breach in brain vasculature.
authors.affiliation: Department of Neurology, S507 Biomedical Science Tower, University of Pittsburgh, Pittsburgh PA 15213, USA. chenj2@upmc.edu;yqgao@shmu.edu.cn.
authors.forename: Rehana K
authors.initials: RK
authors.lastname: Leak
authors.forename: Lili
authors.initials: L
authors.lastname: Zhang
authors.forename: R Anne
authors.initials: RA
authors.lastname: Stetler
authors.forename: Zhongfang
authors.initials: Z
authors.lastname: Weng
authors.forename: Peiying
authors.initials: P
authors.lastname: Li
authors.forename: G Brandon
authors.initials: GB
authors.lastname: Atkins
authors.forename: Yanqin
authors.initials: Y
authors.lastname: Gao
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000502:physiology*; D001929:Brain Edema / Q000235:genetics / Q000503:physiopathology; D002470:Cell Survival / Q000502:physiology; D016207:Cytokines / Q000378:metabolism; D042783:Endothelial Cells / Q000502:physiology; D055551:HSP27 Heat-Shock Proteins / Q000235:genetics / Q000502:physiology*; D020244:Infarction, Middle Cerebral Artery / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D061251:Primary Cell Culture; D015854:Up-Regulation / Q000502:physiology
chemical_list: D016207:Cytokines; D055551:HSP27 Heat-Shock Proteins; C486699:Hspb2 protein, mouse