Protein kinase C activation modulates reversible increase in cortical blood-brain barrier permeability and tight junction protein expression during hypoxia and posthypoxic reoxygenation

Colin L. Willis, Diana S. Meske, Thomas P. Davis

Research output: Contribution to journalArticle

79 Scopus citations

Abstract

Hypoxia (Hx) is a component of many disease states including stroke. Ischemic stroke occurs when there is a restriction of cerebral blood flow and oxygen to part of the brain. During the ischemic, and subsequent reperfusion phase of stroke, blood-brain barrier (BBB) integrity is lost with tight junction (TJ) protein disruption. However, the mechanisms of Hx and reoxygenation (HR)-induced loss of BBB integrity are not fully understood. We examined the role of protein kinase C (PKC) isozymes in modifying TJ protein expression in a rat model of global Hx. The Hx (6% O2) induced increased hippocampal and cortical vascular permeability to 4 and 10 kDa dextran fluorescein isothiocyanate (FITC) and endogenous rat-IgG. Cortical microvessels revealed morphologic changes in nPKC- distribution, increased nPKCθ- and aPKC- protein expression, and activation by phosphorylation of nPKC-θ (Thr538) and aPKC- (Thr410) residues after Hx treatment. Claudin-5, occludin, and ZO-1 showed disrupted organization at endothelial cell margins, whereas Western blot analysis showed increased TJ protein expression after Hx. The PKC inhibition with chelerythrine chloride (5 mg/kg intraperitoneally) attenuated Hx-induced hippocampal vascular permeability and claudin-5, PKC ( and ) expression, and phosphorylation. This study supports the hypothesis that nPKC-θ and aPKC- signaling mediates TJ protein disruption resulting in increased BBB permeability.

Original languageEnglish (US)
Pages (from-to)1847-1859
Number of pages13
JournalJournal of Cerebral Blood Flow and Metabolism
Volume30
Issue number11
DOIs
StatePublished - Nov 1 2010

Keywords

  • blood-brain barrier
  • ischemia
  • protein kinase C
  • tight junction
  • vascular permeability

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

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