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Modulation of Rac1 activity by ADMA/DDAH regulates pulmonary endothelial barrier function

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Modulation of Rac1 activity by ADMA/DDAH regulates pulmonary endothelial barrier function. / Wojciak-Stothard, Beata; Torondel, Belen; Zhao, Lan; Renné, Thomas; Leiper, James M.

in: MOL BIOL CELL, Jahrgang 20, Nr. 1, 01.01.2009, S. 33-42.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Wojciak-Stothard, B, Torondel, B, Zhao, L, Renné, T & Leiper, JM 2009, 'Modulation of Rac1 activity by ADMA/DDAH regulates pulmonary endothelial barrier function', MOL BIOL CELL, Jg. 20, Nr. 1, S. 33-42. https://doi.org/10.1091/mbc.E08-04-0395

APA

Wojciak-Stothard, B., Torondel, B., Zhao, L., Renné, T., & Leiper, J. M. (2009). Modulation of Rac1 activity by ADMA/DDAH regulates pulmonary endothelial barrier function. MOL BIOL CELL, 20(1), 33-42. https://doi.org/10.1091/mbc.E08-04-0395

Vancouver

Wojciak-Stothard B, Torondel B, Zhao L, Renné T, Leiper JM. Modulation of Rac1 activity by ADMA/DDAH regulates pulmonary endothelial barrier function. MOL BIOL CELL. 2009 Jan 1;20(1):33-42. https://doi.org/10.1091/mbc.E08-04-0395

Bibtex

@article{37e54cdbb0de4d0c991dc81f09af1e2b,
title = "Modulation of Rac1 activity by ADMA/DDAH regulates pulmonary endothelial barrier function",
abstract = "Endogenously produced nitric oxide synthase inhibitor, asymmetric methylarginine (ADMA) is associated with vascular dysfunction and endothelial leakage. We studied the role of ADMA, and the enzymes metabolizing it, dimethylarginine dimethylaminohydrolases (DDAH) in the regulation of endothelial barrier function in pulmonary macrovascular and microvascular cells in vitro and in lungs of genetically modified heterozygous DDAHI knockout mice in vivo. We show that ADMA increases pulmonary endothelial permeability in vitro and in in vivo and that this effect is mediated by nitric oxide (NO) acting via protein kinase G (PKG) and independent of reactive oxygen species formation. ADMA-induced remodeling of actin cytoskeleton and intercellular adherens junctions results from a decrease in PKG-mediated phosphorylation of vasodilator-stimulated phosphoprotein (VASP) and a subsequent down-regulation of Rac1 activity. The effects of ADMA on endothelial permeability, Rac1 activation and VASP phosphorylation are prevented by overexpression of active DDAHI and DDAHII, whereas inactive DDAH mutants have no effect. These findings demonstrate for the first time that ADMA metabolism critically determines pulmonary endothelial barrier function by modulating Rac1-mediated remodeling of the actin cytoskeleton and intercellular junctions.",
keywords = "Adherens Junctions, Amidohydrolases, Animals, Antigens, CD, Arginine, Cadherins, Cell Adhesion Molecules, Cells, Cultured, Cyclic GMP-Dependent Protein Kinases, Cytoskeleton, Endothelium, Enzyme Activation, Enzyme Inhibitors, Isoenzymes, Lung, Mice, Mice, Knockout, Microfilament Proteins, Nitric Oxide, Nitric Oxide Synthase, Permeability, Phosphoproteins, Reactive Oxygen Species, Swine, cdc42 GTP-Binding Protein, rac1 GTP-Binding Protein, rhoA GTP-Binding Protein",
author = "Beata Wojciak-Stothard and Belen Torondel and Lan Zhao and Thomas Renn{\'e} and Leiper, {James M}",
year = "2009",
month = jan,
day = "1",
doi = "10.1091/mbc.E08-04-0395",
language = "English",
volume = "20",
pages = "33--42",
journal = "MOL BIOL CELL",
issn = "1059-1524",
publisher = "American Society for Cell Biology",
number = "1",

}

RIS

TY - JOUR

T1 - Modulation of Rac1 activity by ADMA/DDAH regulates pulmonary endothelial barrier function

AU - Wojciak-Stothard, Beata

AU - Torondel, Belen

AU - Zhao, Lan

AU - Renné, Thomas

AU - Leiper, James M

PY - 2009/1/1

Y1 - 2009/1/1

N2 - Endogenously produced nitric oxide synthase inhibitor, asymmetric methylarginine (ADMA) is associated with vascular dysfunction and endothelial leakage. We studied the role of ADMA, and the enzymes metabolizing it, dimethylarginine dimethylaminohydrolases (DDAH) in the regulation of endothelial barrier function in pulmonary macrovascular and microvascular cells in vitro and in lungs of genetically modified heterozygous DDAHI knockout mice in vivo. We show that ADMA increases pulmonary endothelial permeability in vitro and in in vivo and that this effect is mediated by nitric oxide (NO) acting via protein kinase G (PKG) and independent of reactive oxygen species formation. ADMA-induced remodeling of actin cytoskeleton and intercellular adherens junctions results from a decrease in PKG-mediated phosphorylation of vasodilator-stimulated phosphoprotein (VASP) and a subsequent down-regulation of Rac1 activity. The effects of ADMA on endothelial permeability, Rac1 activation and VASP phosphorylation are prevented by overexpression of active DDAHI and DDAHII, whereas inactive DDAH mutants have no effect. These findings demonstrate for the first time that ADMA metabolism critically determines pulmonary endothelial barrier function by modulating Rac1-mediated remodeling of the actin cytoskeleton and intercellular junctions.

AB - Endogenously produced nitric oxide synthase inhibitor, asymmetric methylarginine (ADMA) is associated with vascular dysfunction and endothelial leakage. We studied the role of ADMA, and the enzymes metabolizing it, dimethylarginine dimethylaminohydrolases (DDAH) in the regulation of endothelial barrier function in pulmonary macrovascular and microvascular cells in vitro and in lungs of genetically modified heterozygous DDAHI knockout mice in vivo. We show that ADMA increases pulmonary endothelial permeability in vitro and in in vivo and that this effect is mediated by nitric oxide (NO) acting via protein kinase G (PKG) and independent of reactive oxygen species formation. ADMA-induced remodeling of actin cytoskeleton and intercellular adherens junctions results from a decrease in PKG-mediated phosphorylation of vasodilator-stimulated phosphoprotein (VASP) and a subsequent down-regulation of Rac1 activity. The effects of ADMA on endothelial permeability, Rac1 activation and VASP phosphorylation are prevented by overexpression of active DDAHI and DDAHII, whereas inactive DDAH mutants have no effect. These findings demonstrate for the first time that ADMA metabolism critically determines pulmonary endothelial barrier function by modulating Rac1-mediated remodeling of the actin cytoskeleton and intercellular junctions.

KW - Adherens Junctions

KW - Amidohydrolases

KW - Animals

KW - Antigens, CD

KW - Arginine

KW - Cadherins

KW - Cell Adhesion Molecules

KW - Cells, Cultured

KW - Cyclic GMP-Dependent Protein Kinases

KW - Cytoskeleton

KW - Endothelium

KW - Enzyme Activation

KW - Enzyme Inhibitors

KW - Isoenzymes

KW - Lung

KW - Mice

KW - Mice, Knockout

KW - Microfilament Proteins

KW - Nitric Oxide

KW - Nitric Oxide Synthase

KW - Permeability

KW - Phosphoproteins

KW - Reactive Oxygen Species

KW - Swine

KW - cdc42 GTP-Binding Protein

KW - rac1 GTP-Binding Protein

KW - rhoA GTP-Binding Protein

U2 - 10.1091/mbc.E08-04-0395

DO - 10.1091/mbc.E08-04-0395

M3 - SCORING: Journal article

C2 - 18923147

VL - 20

SP - 33

EP - 42

JO - MOL BIOL CELL

JF - MOL BIOL CELL

SN - 1059-1524

IS - 1

ER -