Activation of PKC modulates blood-brain barrier endothelial cell permeability changes induced by hypoxia and posthypoxic reoxygenation

被引:65
作者
Fleegal, MA
Hom, S
Borg, LK
Davis, TP
机构
[1] Univ Arizona, Dept Med Pharmacol, Tucson, AZ USA
[2] Univ Arizona, Program Physiol Sci, Tucson, AZ USA
来源
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY | 2005年 / 289卷 / 05期
关键词
protein kinase C; paracellular; neurovascular unit; rat;
D O I
10.1152/ajpheart.00495.2005
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
The blood- brain barrier ( BBB) is a metabolic and physiological barrier important for maintaining brain homeostasis. The aim of this study was to determine the role of PKC activation in BBB paracellular permeability changes induced by hypoxia and posthypoxic reoxygenation using in vitro and in vivo BBB models. In rat brain microvessel endothelial cells ( RMECs) exposed to hypoxia ( 1% O-2- 99% N-2; 24 h), a significant increase in total PKC activity was observed, and this was reduced by posthypoxic reoxygenation ( 95% room air- 5% CO2) for 2 h. The expression of PKC- beta II, PKC- gamma, PKC- eta, PKC- mu, and PKC-lambda also increased following hypoxia ( 1% O-2- 99% N-2; 24 h), and these protein levels remained elevated following posthypoxic reoxygenation ( 95% room air- 5% CO2; 2 h). Increases in the expression of PKC-epsilon and PKC-xi were also observed following posthypoxic reoxygenation ( 95% room air- 5% CO2; 2 h). Moreover, inhibition of PKC with chelerythrine chloride ( 10 mu M) attenuated the hypoxia-induced increases in [C-14] sucrose permeability. Similar to what was observed in RMECs, total PKC activity was also stimulated in cerebral microvessels isolated from rats exposed to hypoxia ( 6% O-2- 94% N-2; 1 h) and posthypoxic reoxygenation ( room air; 10 min). In contrast, hypoxia ( 6% O-2- 94% N-2; 1 h) and posthypoxic reoxygenation ( room air; 10 min) significantly increased the expression levels of only PKC-gamma and PKC-theta in the in vivo hypoxia model. These data demonstrate that hypoxia- induced BBB paracellular permeability changes occur via a PKC- dependent mechanism, possibly by differentially regulating the protein expression of the 11 PKC isozymes.
引用
收藏
页码:H2012 / H2019
页数:8
相关论文
共 49 条
[1]  
Abbruscato TJ, 1999, J PHARMACOL EXP THER, V289, P668
[2]   Protein expression of brain endothelial cell E-cadherin after hypoxia/aglycemia: influence of astrocyte contact [J].
Abbruscato, TJ ;
Davis, TP .
BRAIN RESEARCH, 1999, 842 (02) :277-286
[3]  
Akopov Sergey, 2003, J Am Med Dir Assoc, V4, pS127
[4]   Protein kinase C regulates the phosphorylation and cellular localization of occludin [J].
Andreeva, AY ;
Krause, E ;
Müller, EC ;
Blasig, IE ;
Utepbergenov, DI .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (42) :38480-38486
[5]   Critical role of the atypical λ isoform of protein kinase C (PKC-λ) in oxidant-induced disruption of the microtubule cytoskeleton and barrier function of intestinal epithelium [J].
Banan, A ;
Zhang, LJ ;
Farhadi, A ;
Fields, JZ ;
Shaikh, M ;
Forsyth, CB ;
Choudhary, S ;
Keshavarzian, A .
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2005, 312 (02) :458-471
[6]   θ-Isoform of PKC is required for alterations in cytoskeletal dynamics and barrier permeability in intestinal epithelium:: a novel function for PKC-θ [J].
Banan, A ;
Zhang, LJ ;
Shaikh, M ;
Fields, JZ ;
Farhadi, A ;
Keshavarzian, A .
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY, 2004, 287 (01) :C218-C234
[7]   PKC-β1 isoform activation is required for EGF-induced NF-κB inactivation and IκBα stabilization and protection of F-actin assembly and barrier function in enterocyte monolayers [J].
Banan, A ;
Zhang, LJ ;
Farhadi, A ;
Fields, JZ ;
Shaikh, M ;
Keshavarzian, A .
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY, 2004, 286 (03) :C723-C738
[8]   ζ isoform of protein kinase C prevents oxidant-induced nuclear factor-κB activation and I-κBα degradation:: A fundamental mechanism for epidermal growth factor protection of the microtubule cytoskeleton and intestinal barrier integrity [J].
Banan, A ;
Fields, JZ ;
Zhang, LJ ;
Shaikh, M ;
Farhadi, A ;
Keshavarzian, A .
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2003, 307 (01) :53-66
[9]   The δ-isoform of protein kinase C causes inducible nitric-oxide synthase and nitric oxide up-regulation:: Key mechanism for oxidant-induced carbonylation, nitration, and disassembly of the microtubule cytoskeleton and hyperpermeability of barrier of intestinal epithelia [J].
Banan, A ;
Farhadi, A ;
Fields, JZ ;
Zhang, LJ ;
Shaikh, M ;
Keshavarzian, A .
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2003, 305 (02) :482-494
[10]   PKC-ζ prevents oxidant-induced iNOS upregulation and protects the microtubules and gut barrier integrity [J].
Banan, A ;
Zhang, L ;
Fields, JZ ;
Farhadi, A ;
Talmage, DA ;
Keshavarzian, A .
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY, 2002, 283 (04) :G909-G922