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Protein kinase C activation modulates reversible increase in cortical blood-brain barrier permeability and tight junction protein expression during hypoxia and posthypoxic reoxygenation.
J Cereb Blood Flow Metab 2010; 30(11):1847-59JC

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% O(2)) 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-θ distribution, increased nPKC-θ and aPKC-ζ protein expression, and activation by phosphorylation of nPKC-θ (Thr538) and aPKC-ζ (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 (θ and ζ) expression, and phosphorylation. This study supports the hypothesis that nPKC-θ and aPKC-ζ signaling mediates TJ protein disruption resulting in increased BBB permeability.

Authors+Show Affiliations

Department of Pharmacology, College of Medicine, University of Arizona, Tucson, Arizona, USA. cwillis1@une.eduNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

20700133

Citation

Willis, Colin L., et al. "Protein Kinase C Activation Modulates Reversible Increase in Cortical Blood-brain Barrier Permeability and Tight Junction Protein Expression During Hypoxia and Posthypoxic Reoxygenation." Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism, vol. 30, no. 11, 2010, pp. 1847-59.
Willis CL, Meske DS, Davis TP. Protein kinase C activation modulates reversible increase in cortical blood-brain barrier permeability and tight junction protein expression during hypoxia and posthypoxic reoxygenation. J Cereb Blood Flow Metab. 2010;30(11):1847-59.
Willis, C. L., Meske, D. S., & Davis, T. P. (2010). Protein kinase C activation modulates reversible increase in cortical blood-brain barrier permeability and tight junction protein expression during hypoxia and posthypoxic reoxygenation. Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism, 30(11), pp. 1847-59. doi:10.1038/jcbfm.2010.119.
Willis CL, Meske DS, Davis TP. Protein Kinase C Activation Modulates Reversible Increase in Cortical Blood-brain Barrier Permeability and Tight Junction Protein Expression During Hypoxia and Posthypoxic Reoxygenation. J Cereb Blood Flow Metab. 2010;30(11):1847-59. PubMed PMID: 20700133.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Protein kinase C activation modulates reversible increase in cortical blood-brain barrier permeability and tight junction protein expression during hypoxia and posthypoxic reoxygenation. AU - Willis,Colin L, AU - Meske,Diana S, AU - Davis,Thomas P, Y1 - 2010/08/11/ PY - 2010/8/12/entrez PY - 2010/8/12/pubmed PY - 2010/12/14/medline SP - 1847 EP - 59 JF - Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism JO - J. Cereb. Blood Flow Metab. VL - 30 IS - 11 N2 - 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% O(2)) 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-θ distribution, increased nPKC-θ and aPKC-ζ protein expression, and activation by phosphorylation of nPKC-θ (Thr538) and aPKC-ζ (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 (θ and ζ) expression, and phosphorylation. This study supports the hypothesis that nPKC-θ and aPKC-ζ signaling mediates TJ protein disruption resulting in increased BBB permeability. SN - 1559-7016 UR - https://www.unboundmedicine.com/medline/citation/20700133/Protein_kinase_C_activation_modulates_reversible_increase_in_cortical_blood_brain_barrier_permeability_and_tight_junction_protein_expression_during_hypoxia_and_posthypoxic_reoxygenation_ L2 - http://journals.sagepub.com/doi/full/10.1038/jcbfm.2010.119?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -