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Phospholipase D Signaling Mediates Reactive Oxygen Species-induced Lung Endothelial Barrier Dysfunction

P. Usatyuk, Sainath R. Kotha, N. Parinandi, V. Natarajan
Published 2013 · Biology, Medicine

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Reactive oxygen species (ROS) have emerged as critical players in the pathophysiology of pulmonary disorders and diseases. Earlier, we have demonstrated that ROS stimulate lung endothelial cell (EC) phospholipase D (PLD) that generates phosphatidic acid (PA), a second messenger involved in signal transduction. In the current study, we investigated the role of PLD signaling in the ROS-induced lung vascular EC barrier dysfunction. Our results demonstrated that hydrogen peroxide (H2O2), a typical physiological ROS, induced PLD activation and altered the barrier function in bovine pulmonary artery ECs (BPAECs). 1-Butanol, the quencher of PLD, generated PA leading to the formation of physiologically inactive phosphatidyl butanol but not its biologically inactive analog, 2-butanol, blocked the H2O2-mediated barrier dysfunction. Furthermore, cell permeable C2 ceramide, an inhibitor of PLD but not the C2 dihydroceramide, attenuated the H2O2-induced PLD activation and enhancement of paracellular permeability of Evans blue conjugated albumin across the BPAEC monolayers. In addition, transfection of BPAECs with adenoviral constructs of hPLD1 and mPLD2 mutants attenuated the H2O2-induced barrier dysfunction, cytoskeletal reorganization and distribution of focal adhesion proteins. For the first time, this study demonstrated that the PLD-generated intracellular bioactive lipid signal mediator, PA, played a critical role in the ROS-induced barrier dysfunction in lung vascular ECs. This study also underscores the importance of PLD signaling in vascular leak and associated tissue injury in the etiology of lung diseases among critically ill patients encountering oxygen toxicity and excess ROS production during ventilator-assisted breathing.
This paper references
Hydrogen peroxide regulation of endothelial function: origins, mechanisms, and consequences.
Hua Cai (2005)
Phospholipase D/phosphatidic acid signal transduction: Role and physiological significance in lung
R. Cummings (2004)
Phospholipase D Activity Is Required for Actin Stress Fiber Formation in Fibroblasts
Y. Kam (2001)
Involvement of phospholipases D 1 and D 2 in sphingosine 1-phosphate-induced ERK ( extracellular-signal-regulated kinase ) activation and interleukin-8 secretion in human bronchial epithelial cells
L. Wang
Rho GTPases and the regulation of endothelial permeability.
B. Wojciak-Stothard (2002)
Hydroxyalkenals and oxidized phospholipids modulation of endothelial cytoskeleton, focal adhesion and adherens junction proteins in regulating endothelial barrier function.
P. Usatyuk (2012)
Role of protein tyrosine phosphorylation in H2O2-induced activation of endothelial cell phospholipase D.
V. Natarajan (1996)
Regulation of Endothelial Junctional Permeability
E. Vandenbroucke (2008)
Tyrosine kinases and calcium dependent activation of endothelial cell phospholipase D by diperoxovanadate
V. Natarajan (2004)
Involvement of phospholipases D1 and D2 in sphingosine 1-phosphate-induced ERK (extracellular-signal-regulated kinase) activation and interleukin-8 secretion in human bronchial epithelial cells.
L. Wang (2002)
Cross talk between focal adhesion kinase and cadherins: role in regulating endothelial barrier function.
S. Quadri (2012)
Phospholipase D activation in endothelial cells is redox sensitive.
N. Parinandi (1999)
Role of Mitogen-activated Protein Kinases in 4-Hydroxy-2-nonenal-induced Actin Remodeling and Barrier Function in Endothelial Cells*
P. Usatyuk (2004)
Phosphatidic acid directly activates endothelial cell protein kinase C.
J. Stasek (1993)
regulating endothelial barrier function
H Lum (2012)
Phospholipase D1 is threonine-phosphorylated in human-airway epithelial cells stimulated by sphingosine-1-phosphate by a mechanism involving Src tyrosine kinase and protein kinase Cdelta.
A. Ghelli (2002)
Regulation of reactive oxygen species-induced endothelial cell-cell and cell-matrix contacts by focal adhesion kinase and adherens junction proteins.
P. Usatyuk (2005)
Agonist-induced activation of phospholipase D in bovine pulmonary artery endothelial cells: regulation by protein kinase C and calcium.
V. Natarajan (1993)
Hydrogen peroxide stimulates tyrosine phosphorylation of focal adhesion kinase in vascular endothelial cells.
S. Vepa (1999)
The enhancement by wortmannin of protein kinase C-dependent activation of phospholipase D in vascular endothelial cells.
V. Natarajan (1997)
Oxidant stress and endothelial cell dysfunction.
H. Lum (2001)
Regulation of phospholipase D by tyrosine kinases.
V. Natarajan (1996)
Phospholipase D2 regulates endothelial permeability through cytoskeleton reorganization and occludin downregulation.
Caroline Zeiller (2009)
Phospholipase D is involved in myogenic differentiation through remodeling of actin cytoskeleton.
H. Komati (2005)
The role of adherens junctions and VE-cadherin in the control of vascular permeability
E. Dejana (2008)
Akt activates NOS3 and separately restores barrier integrity in H2O2-stressed human cardiac microvascular endothelium.
A. Dossumbekova (2008)
Protein kinase C ‐ epsilon regulates sphingosine 1 ‐ phosphate ‐ mediated migration of human lung endothelial cells through activation of phospholipase D 2 , protein kinase C ‐ zeta and Rac 1
I Gorshkova (2008)
Oxidative stress and redox regulation of phospholipase D in myocardial disease.
P. Tappia (2006)
The Regulation of Vascular Endothelial Growth Factor-induced Microvascular Permeability Requires Rac and Reactive Oxygen Species*
E. Monaghan-Benson (2009)
Phospholipase D 2 ( PLD 2 ) is a guanine nucleotide exchange factor ( GEF ) for the GTPase Rac 2
M Mahankali (2011)
Protein Kinase C-ϵ Regulates Sphingosine 1-Phosphate-mediated Migration of Human Lung Endothelial Cells through Activation of Phospholipase D2, Protein Kinase C-ζ, and Rac1*
I. Gorshkova (2008)
[Phospholipase D].
T. Taki (1986)
Diperoxovanadate alters endothelial cell focal contacts and barrier function: role of tyrosine phosphorylation.
J. Garcia (2000)
Pulmonary circulation
G. Bongartz (1998)
Role of Ca2+ in diperoxovanadate-induced cytoskeletal remodeling and endothelial cell barrier function.
P. Usatyuk (2003)
Activation of endothelial cell phospholipase D by sphingosine and sphingosine-1-phosphate.
V. Natarajan (1994)
Semin Cell Dev Biol
Mj Wakelam (1997)
Role of p38 MAP kinase in diperoxovanadate-induced phospholipase D activation in endothelial cells.
V. Natarajan (2001)
Induction of endothelial monolayer permeability by phosphatidate
D. English (1999)
Role of protein kinase Czeta in thrombin-induced RhoA activation and inter-endothelial gap formation of human dermal microvessel endothelial cell monolayers.
R. Minshall (2010)
Role of Src kinase in diperoxovanadate-mediated activation of phospholipase D in endothelial cells.
N. Parinandi (2001)
Signaling mechanisms regulating endothelial permeability.
D. Mehta (2006)
A morphological biosensor for mammalian cells
I. Giaever (1993)
Inter-regulatory dynamics of phospholipase D and the actin cytoskeleton.
S. Rudge (2009)
PLD regulates lung endothelial permeability
Vascular endothelial-cadherin regulates cytoskeletal tension, cell spreading, and focal adhesions by stimulating RhoA.
C. Nelson (2004)
Hydrogen peroxide: a signaling messenger.
J. Stone (2006)
Hyperoxia alters phorbol ester-induced phospholipase D activation in bovine lung microvascular endothelial cells.
S. Roy (2003)
Phospholipase D2 induces stress fiber formation through mediating nucleotide exchange for RhoA.
Hyeona Jeon (2011)
Regulation of endothelial cell myosin light chain kinase by Rho, cortactin, and p60(src).
J. Garcia (1999)
Pulmonary Fibrosis Inducer, Bleomycin, Causes Redox-Sensitive Activation of Phospholipase D and Cytotoxicity Through Formation of Bioactive Lipid Signal Mediator, Phosphatidic Acid, in Lung Microvascular Endothelial Cells
R. Patel (2011)
Phospholipase D Activation by Sphingosine 1-Phosphate Regulates Interleukin-8 Secretion in Human Bronchial Epithelial Cells*
R. Cummings (2002)
Source of Support: Nil, Conflict of Interest: None declared
Phospholipase D-mediated Activation of IQGAP1 through Rac1 Regulates Hyperoxia-induced p47phox Translocation and Reactive Oxygen Species Generation in Lung Endothelial Cells*
P. Usatyuk (2009)
Phospholipase D2 (PLD2) is a guanine nucleotide exchange factor (GEF) for the GTPase Rac2
Madhu Mahankali (2011)
Phospholipase D and signal transduction in mammalian cells.
V. Natarajan (1996)
Phospholipase D. Biochem Cell Biol 2004;82:225‐53
M McDermott (2004)
Actin stress fibres
S. Pellegrin (2007)
Novel Role for Non-muscle Myosin Light Chain Kinase (MLCK) in Hyperoxia-induced Recruitment of Cytoskeletal Proteins, NADPH Oxidase Activation, and Reactive Oxygen Species Generation in Lung Endothelium*
P. Usatyuk (2012)
Oxidants and signal transduction in vascular endothelium.
V. Natarajan (1995)
Rho and Rac but not Cdc42 regulate endothelial cell permeability.
B. Wojciak-Stothard (2001)
Role of p 38 MAP kinase in diperoxovanadate ‐ induced phospholipase D activation in endothelial cells
V Natarajan (2001)
Regulation of Hyperoxia-induced NADPH Oxidase Activation in Human Lung Endothelial Cells by the Actin Cytoskeleton and Cortactin*
P. Usatyuk (2007)
Type I phosphatidylinositol 4-phosphate 5-kinase isoforms are specifically stimulated by phosphatidic acid.
G. H. Jenkins (1994)
Regulation of endothelial cell myosin light chain kinase by Rho, cortactin, and p60 src.
J. Garcia (1999)
Re-evaluation of Evans Blue dye as a marker of albumin clearance in murine models of acute lung injury.
J. Moitra (2007)
Mechanisms of H2O2-induced oxidative stress in endothelial cells.
Christian H. Coyle (2006)
Involvement of c-Src in diperoxovanadate-induced endothelial cell barrier dysfunction.
S. Shi (2000)
Biochem Cell Biol
M Mcdermott (2004)
Role of reactive oxygen and nitrogen species in the vascular responses to inflammation.
P. Kvietys (2012)
Stimulation of actin stress fibre formation mediated by activation of phospholipase D
M. Cross (1996)
Redox regulation of reactive oxygen species-induced p38 MAP kinase activation and barrier dysfunction in lung microvascular endothelial cells.
P. Usatyuk (2003)
Phospholipase D1 Regulates Cell Migration in a Lipase Activity-independent Manner*
J. Kim (2006)
Metabolites of the phospholipase D pathway regulate H2O2‐induced filamin redistribution in endothelial cells
L. E. Hastie (1998)

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Phospholipase D and the Mitogen Phosphatidic Acid in Human Disease: Inhibitors of PLD at the Crossroads of Phospholipid Biology and Cancer.
J. Gomez-Cambronero (2019)
Sphingolipids Signaling in Lamellipodia Formation and Enhancement of Endothelial Barrier Function.
P. Fu (2018)
Phospholipase D2 restores endothelial barrier function by promoting PTPN14-mediated VE-cadherin dephosphorylation
P. Fu (2020)
Inhibited Insulin Signaling in Mouse Hepatocytes Is Associated with Increased Phosphatidic Acid but Not Diacylglycerol*
Chongben Zhang (2014)
Neutrophil‐mediated vascular barrier injury: Role of neutrophil extracellular traps
J. Meegan (2017)
Resolvin D-series regulates Phospholipase D both during inflammation and resolution by modulating phagocyte functions
Ramya Ganesan (2019)
LAURDAN fluorescence and phasor plots reveal the effects of a H2O2 bolus in NIH‐3T3 fibroblast membranes dynamics and hydration
Leonel Malacrida (2018)
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