Role of Cadherin Internalization in Hydrogen Peroxide-Mediated Endothelial Permeability

Kevil, Christopher G.; Ohno, Norioki; Gute, Dean C.; Okayama, Naotsuka; Robinson, Sarah; Chaney, Ed; Alexander, John

doi:10.1016/s0891-5849(97)00433-4

Cited by 85 publications

(75 citation statements)

References 25 publications

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“…Reduced VE-cadherin protein content was also detected; a finding that may in part be responsible for the observed intercellular gaps. An increased plasma concentration of VE-cadherin has been associated with coronary atherosclerosis (Soeki et al, 2004), and in vitro studies have shown that hydrogen peroxide induces internalization of VE-cadherin and gap formation (Kevil et al, 1998). Hence, the decreased VE-cadherin may be due to internalization and degradation or release into the cell culture medium.…”

Section: Discussionmentioning

confidence: 99%

Activation of protein kinase C and disruption of endothelial monolayer integrity by sodium arsenite—Potential mechanism in the development of atherosclerosis

Pereira

Coffin

Beall

2007

Toxicology and Applied Pharmacology

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Arsenic exposure has been shown to exacerbate atherosclerosis, beginning with activation of the endothelium that lines the vessel wall. Endothelial barrier integrity is maintained by proteins of the adherens junction (AJ) such as vascular endothelial cadherin (VE-cadherin) and β-catenin and their association with the actin cytoskeleton. In the present study, human aortic endothelial cells (HAECs) were exposed to 1, 5 and 10 μM sodium arsenite [As(III)] for 1, 6, 12 and 24 h, and the effects on endothelial barrier integrity were determined. Immunofluorescence studies revealed formation of actin stress fibers and non-uniform VE-cadherin and β-catenin staining at cell-cell junctions that were concentration and time-dependent. Intercellular gaps were observed with a measured increase in endothelial permeability. In addition, concentration-dependent increases in tyrosine phosphorylation (PY) of β-catenin and activation of protein kinase Cα (PKCα) were observed. Inhibition of PKCα restored VE-cadherin and β-catenin staining at cell-cell junctions and abolished the As(III) induced formation of actin stress fibers and intercellular gaps. Endothelial permeability and PY of β-catenin were also reduced to basal levels. These results demonstrate that As(III) induces activation of PKCα, which leads to increased PY of β-catenin downstream of PKCα activation. Phosphorylation of β-catenin plausibly severs the association of VE-cadherin and β-catenin, which along with formation of actin stress fibers, results in intercellular gap formation and increased endothelial permeability. To the best of our knowledge, this is the first report demonstrating that As(III) causes a loss of endothelial monolayer integrity, which potentially could contribute to the development of atherosclerosis.

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Section: Discussionmentioning

confidence: 99%

Activation of protein kinase C and disruption of endothelial monolayer integrity by sodium arsenite—Potential mechanism in the development of atherosclerosis

Pereira

Coffin

Beall

2007

Toxicology and Applied Pharmacology

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“…Energy depletion and exposure to oxidants increased endothelial permeability and intercellular gap formation (24,34). Also, increases in endothelial permeability were associated with internalization of VE-cadherin from endothelial adherens junctions (2,29,48). Energy depletion of endothelial cells leads to increased cellcell separation and macromolecule permeability of the endothelial cell barrier due to rapid, but reversible disintegration of F-actin cytoskeletal structures (24).…”

Section: Discussionmentioning

confidence: 99%

Cofilin mediates ATP depletion-induced endothelial cell actin alterations

Suurna¹,

Ashworth²,

Hosford³

et al. 2006

American Journal of Physiology-Renal Physiology

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Ischemia and sepsis lead to endothelial cell damage, resulting in compromised microvascular flow in many organs. Much remains to be determined regarding the intracellular structural events that lead to endothelial cell dysfunction. To investigate potential actin cytoskeletal-related mechanisms, ATP depletion was induced in mouse pancreatic microvascular endothelial cells (MS1). Fluorescent imaging and biochemical studies demonstrated a rapid and progressive increase in F-actin along with a decrease in G-actin at 60 min. Confocal microscopic analysis showed ATP depletion resulted in destruction of actin stress fibers and accumulation of F-actin aggregates. We hypothesized these actin alterations were secondary to dephosphorylation/activation of actin-depolymerizing factor (ADF)/cofilin proteins. Cofilin, the predominant isoform expressed in MS1 cells, was rapidly dephosphorylated/activated during ATP depletion. To directly investigate the role of cofilin activation on the actin cytoskeleton during ischemia, MS1 cells were infected with adenoviruses containing the cDNAs for wild-type Xenopus laevis ADF/cofilin green fluorescent protein [XAC(wt)-GFP], GFP, and the constitutively active and inactive isoforms XAC(S3A)-GFP and XAC(S3E)-GFP. The rate and extent of cortical actin destruction and actin aggregate formation were increased in ATP-depleted XAC(wt)-GFP- and XAC(S3A)-GFP-expressing cells, whereas increased actin stress fibers were observed in XAC(S3E)-GFP-expressing cells. To investigate the upstream signaling pathway of ADF/cofilin, LIM kinase 1-GFP (LIMK1-GFP) was expressed in MS1 cells. Cells expressing LIMK1-GFP protein had higher levels of phosphorylated ADF/cofilin, increased stress fibers, and delayed F-actin cytoskeleton destruction during ATP depletion. These results strongly support the importance of cofilin regulation in ischemia-induced endothelial cell actin cytoskeleton alterations leading to cell damage and microvascular dysfunction.

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“…The intracellular signal pathways that cause an increase in endothelial permeability are still not completely defined despite extensive study of the effect of the above mediators of endothelial dysfunction. Importantly, however, PKC is now known to be a necessary part in the regulation of endothelial permeability and edema formation induced by three known mediators of RDS: H 2 O 2 , thrombin, and TNF-␣ (7,23,50,54,87,107,164,165). This review highlights the role of PKC in the endothelial barrier alteration induced by H 2 O 2 , thrombin, and TNF-␣.…”

Section: Pkc In Lung Injurymentioning

confidence: 99%

“…In isolated guinea pig lungs, perfusion with low concentrations of H 2 O 2 causes increases in P pa , P pc , lung weight, and K fc that are prevented by the PKC inhibitor H7 (68), but not by HA1004 (68,80). PKC is a primary mediator for reactive oxygen speciesinduced endothelial barrier dysfunction because H 2 O 2 -induced increases in endothelial permeability to protein are prevented by inhibitors of PKC activity (87,164,165). In human saphenous vein endothelial cells, during exposure to high concentrations of H 2 O 2 (10 mM), the expression and regulation of PKC-␣, PKC-⑀, and PKC-isotypes were investigated.…”

Section: Pkc In Reactive Oxygen Species-induced Lung Endothelial Injurymentioning

confidence: 99%

Protein kinase C modulates pulmonary endothelial permeability: a paradigm for acute lung injury

Siflinger-Birnboim

Johnson

2003

American Journal of Physiology-Lung Cellular and Molecular Phys

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The intracellular serine/threonine kinase protein kinase C (PKC) has an important role in the genesis of pulmonary edema. This review discusses the PKC-mediated mechanisms that participate in the pulmonary endothelial response to agents involved in lung injury characteristic of the respiratory distress syndrome. Thus the paradigms of PKC-induced lung injury are discussed within the context of pulmonary transvascular fluid exchange. We focus on the signal transduction pathways that are modulated by PKC and their effect on lung endothelial permeability. Specifically, α-thrombin, tumor necrosis factor (TNF)-α, and reactive oxygen species are discussed because of their well-established roles in both human and experimental lung injury. We conclude that PKC, most likely PKC-α, is a primary supporter for lung endothelial injury in response to α-thrombin, TNF-α, and reactive oxygen species.

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Role of Cadherin Internalization in Hydrogen Peroxide-Mediated Endothelial Permeability

Cited by 85 publications

References 25 publications

Activation of protein kinase C and disruption of endothelial monolayer integrity by sodium arsenite—Potential mechanism in the development of atherosclerosis

Activation of protein kinase C and disruption of endothelial monolayer integrity by sodium arsenite—Potential mechanism in the development of atherosclerosis

Cofilin mediates ATP depletion-induced endothelial cell actin alterations

Protein kinase C modulates pulmonary endothelial permeability: a paradigm for acute lung injury

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