Role of PKCβII and PKCδ in blood–brain barrier permeability during aglycemic hypoxia

Kim, Young-Ae; Park, Sung Lyea; Kim, Miyoung; Lee, Soo Hwan; Baik, Eun Joo; Moon, Chang-Hyun

doi:10.1016/j.neulet.2009.11.007

Cited by 29 publications

(25 citation statements)

References 22 publications

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“…We further noted that chemical and molecular inhibition in vivo and in vitro results in pulmonary edema formation and endothelial barrier dysfunction through reduced RhoA-GTPasemediated disruption of stress fibers and focal contacts (15,21), respectively. Similar to our studies, PKC␦ inhibition promoted endothelial barrier dysfunction in coronary artery and brainderived endothelial monolayers (9,20). Conversely, PKC␦ inhibition has been correlated with a barrier-protective role.…”

supporting

confidence: 90%

Genetic disruption of protein kinase Cδ reduces endotoxin-induced lung injury

Chichger

Grinnell

Casserly

et al. 2012

American Journal of Physiology-Lung Cellular and Molecular Phys

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of acute lung injury and acute respiratory distress syndrome is characterized by sequestration of leukocytes in lung tissue, disruption of capillary integrity, and pulmonary edema. PKC␦ plays a critical role in RhoA-mediated endothelial barrier function and inflammatory responses. We used mice with genetic deletion of PKC␦ (PKC␦ Ϫ/Ϫ ) to assess the role of PKC␦ in susceptibility to LPS-induced lung injury and pulmonary edema. Under baseline conditions or in settings of increased capillary hydrostatic pressures, no differences were noted in the filtration coefficients (kf) or wet-to-dry weight ratios between PKC␦ ϩ/ϩ and PKC␦ Ϫ/Ϫ mice. However, at 24 h after exposure to LPS, the k f values were significantly higher in lungs isolated from PKC␦ ϩ/ϩ than PKC␦ Ϫ/Ϫ mice. In addition, bronchoalveolar lavage fluid obtained from LPS-exposed PKC␦ ϩ/ϩ mice displayed increased protein and cell content compared with LPS-exposed PKC␦ Ϫ/Ϫ mice, but similar changes in inflammatory cytokines were measured. Histology indicated elevated LPS-induced cellularity and inflammation within PKC␦ ϩ/ϩ mouse lung parenchyma relative to PKC␦ Ϫ/Ϫ mouse lungs. Transient overexpression of catalytically inactive PKC␦ cDNA in the endothelium significantly attenuated LPS-induced endothelial barrier dysfunction in vitro and increased kf lung values in PKC␦ ϩ/ϩ mice. However, transient overexpression of wild-type PKC␦ cDNA in PKC␦ Ϫ/Ϫ mouse lung vasculature did not alter the protective effects of PKC␦ deficiency against LPS-induced acute lung injury. We conclude that PKC␦ plays a role in the pathological progression of endotoxin-induced lung injury, likely mediated through modulation of inflammatory signaling and pulmonary vascular barrier function. endothelium; pulmonary edema; lipopolysaccharide; acute lung injury ACUTE RESPIRATORY DISTRESS syndrome (ARDS) is a major cause of morbidity and mortality in sepsis and severe pneumonia (26). Transudation of vascular fluid and protein from the pulmonary capillary lumen into the interstitium and alveolar air spaces impairs gas exchange, decreases lung compliance, and initiates a cascade of inflammatory events that leads to respiratory failure. This cascade is often characterized by sequestration of leukocytes in lung tissues, intravascular coagulation, and disruption of capillary integrity, leading to pulmonary edema (4).The vascular endothelium is a critical target for an endotoxin such as LPS, an established inflammatory and edemagenic agent. Circulating levels of LPS are elevated in patients with severe pneumonia or sepsis and can be used as a predictor of the development of ARDS (14).PKC␦ plays an important role in the maintenance of the lung vascular barrier. We observed enhanced endothelial barrier function following PKC␦ overexpression in vitro, effects that were mediated through the RhoA-GTPase pathway (21). We further noted that chemical and molecular inhibition in vivo and in vitro results in pulmonary edema formation and endothelial barrier dysfunction through reduced RhoA-GTPasemediated disrup...

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supporting

confidence: 90%

Genetic disruption of protein kinase Cδ reduces endotoxin-induced lung injury

Chichger

Grinnell

Casserly

et al. 2012

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…As mechanisms underlying the disruption of TJ proteins under pathological conditions, rearrangement of intracellular localization and/or alterations of TJ expression levels have been suggested (Wang et al, 2001;Mark and Davis, 2002). In our recent study, the expressions of TJ proteins were shown to be unaltered during aglycemic hypoxia (Kim et al, 2010). In addition, the present study showed that the treatment with sabiporide had no effect on the expressions of TJ proteins during hypoxia.…”

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confidence: 43%

The effect of Na+/H+ exchanger-1 inhibition by sabiporide on blood–brain barrier dysfunction after ischemia/hypoxia in vivo and in vitro

2010

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“…Other studies have shown PKC-a, PKC-b, and PKC-d isoform expression to increase with enhanced vascular permeability after cerebral ischemia or inflammatory stimulation (Yuan, 2002;Jiao et al, 2011). In vitro studies have also shown that PKC isozymes including PKC-z, PKC-bII, and PKC-d have a role in endothelial integrity in bEnd.3 cells as well as in Caco-2 and MDCK cultures (Dodane and Kachar, 1996;Kim et al, 2010). In this study, we speculate that the transitory AKT (Thr308) phosphorylation triggers a signaling cascade that culminates in specific PKC isoform (s) activation.…”

Section: Pi3k/akt Modulation Of Claudin-5 Expressionmentioning

confidence: 96%

Biphasic Modulation of Paracellular Claudin-5 Expression in Mouse Brain Endothelial Cells Is Mediated through the Phosphoinositide-3-Kinase/AKT Pathway

Camire

Beaulac

Brule

et al. 2014

J Pharmacol Exp Ther

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Blood-brain barrier (BBB) integrity is compromised in many central nervous system disorders. Complex astrocyte and vascular endothelial cell interactions that regulate BBB integrity may be disturbed in these disorders. We previously showed that systemic administration of 3-chloropropanediol [(S)-(1)-3-chloro-1,2-propanediol] induces a transitory glial fibrillary acidic proteinastrocyte loss, reversible loss of tight junction complexes, and BBB integrity disruption. However, the intracellular signaling mechanisms that induce BBB integrity marker loss are unclear. We hypothesize that 3-chloropropanediol-induced modulation of tight junction protein expression is mediated through the phosphoinositide-3-kinase (PI3K)/AKT pathway. To test this hypothesis, we used a mouse brain endothelial cell line (bEnd.3) exposed to 3-chloropropanediol for up to 3 days. Results showed early reversible loss of sharp paracellular claudin-5 expression 90, 105, and 120 minutes after 3-chloropropanediol (500 mM) treatment. Sharp paracellular claudin-5 profiles were later restored, but lost again by 2 and 3 days after 3-chloropropanediol treatment. Western blot and immunofluorescence studies showed increased p85-PI3K expression and transitory increased AKT (Thr308) phosphorylation at 15 and 30 minutes after 3-chloropropanediol administration. PI3K inhibitors LY294002 [2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one hydrochloride; 2.5-25 mM] and PI-828 [2-(4-morpholinyl)-8-(4-aminopheny)l-4H-1-benzopyran-4-one; 0.1-10 mM] prevented the 3-chloropropanediol-induced AKT (Thr308) phosphorylation and both early and late loss of paracellular claudin-5. However, AKT inhibitors only prevented the early changes in claudin-5 expression. This mechanistic study provides a greater understanding of the intracellular signaling pathways mediating tight junction protein expression and supports a hypothesis that two independent pathways triggered by PI3K mediate early and late loss of paracellular claudin-5 expression.

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Role of PKCβII and PKCδ in blood–brain barrier permeability during aglycemic hypoxia

Cited by 29 publications

References 22 publications

Genetic disruption of protein kinase Cδ reduces endotoxin-induced lung injury

Genetic disruption of protein kinase Cδ reduces endotoxin-induced lung injury

The effect of Na+/H+ exchanger-1 inhibition by sabiporide on blood–brain barrier dysfunction after ischemia/hypoxia in vivo and in vitro

Biphasic Modulation of Paracellular Claudin-5 Expression in Mouse Brain Endothelial Cells Is Mediated through the Phosphoinositide-3-Kinase/AKT Pathway

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