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PMID: 16004987 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

ALK5 and Smad4 are involved in TGF-beta1-induced pulmonary endothelial permeability.

FEBS letters ·Vol. 579 ·No. 18 ·2005-07-18 ·Pages 4031-7

Birukova AA, Adyshev D, Gorshkov B, Birukov KG, Verin AD

Abstract

The ability of inflammatory cytokine TGF-beta1 to alter endothelial cell phenotype suggests its role in the regulation of vascular endothelial cell permeability. We demonstrate that depletion of TGF-beta1 receptor ALK5 and regulatory protein Smad4, but not ALK1 receptor attenuates TGF-beta1-induced permeability increase and significantly inhibits TGF-beta1-induced EC contraction manifested by actin stress fiber formation and increased MLC and MYPT1 phosphorylation. Consistent with these results, EC treatment with SB 431542, an inhibitor of ALK5 but not ALK1 receptor, significantly attenuates TGF-beta1-induced permeability. Thus, our data demonstrate for the first time direct link between TGF-beta1-mediated activation of ALK5/Smad and EC barrier dysfunction.

MeSH Terms
Actins/metabolism Activin Receptors, Type I/metabolism,physiology Animals Benzamides/pharmacology Blotting, Western Cattle Cells, Cultured Cytoskeleton/metabolism DNA-Binding Proteins/physiology Dioxoles/pharmacology Electric Impedance Endothelium, Vascular/cytology,metabolism Lung/metabolism Microscopy, Fluorescence Myosin-Light-Chain Phosphatase/metabolism Myosins/chemistry Permeability Phenotype Phosphorylation Protein Serine-Threonine Kinases RNA, Small Interfering/metabolism Receptor, Transforming Growth Factor-beta Type I Receptors, Transforming Growth Factor beta/metabolism,physiology Reverse Transcriptase Polymerase Chain Reaction Signal Transduction Smad4 Protein Time Factors Trans-Activators/physiology Transforming Growth Factor beta/metabolism Transforming Growth Factor beta1 Tubulin/metabolism
Chemicals
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide Actins Benzamides DNA-Binding Proteins Dioxoles RNA, Small Interfering Receptors, Transforming Growth Factor beta Smad4 Protein TGFB1 protein, human Trans-Activators Transforming Growth Factor beta Transforming Growth Factor beta1 Tubulin Protein Serine-Threonine Kinases Activin Receptors, Type I Receptor, Transforming Growth Factor-beta Type I TGFBR1 protein, human Myosin-Light-Chain Phosphatase PPP1R12A protein, human Myosins
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Birukova Anna A
Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA.
Adyshev Djanibek
Gorshkov Boris
Birukov Konstantin G
Verin Alexander D
Article Info
Journal
FEBS letters
Abbr.
FEBS Lett
ISSN
0014-5793
DOI
10.1016/j.febslet.2005.06.018
Published
2005-07-18
Pages
4031-7
Language
English
Region
England
NLM ID
0155157
Subset
IM
Grants
NHLBI NIH HHS · HL080675 · United States
NHLBI NIH HHS · HL58064 · United States
NHLBI NIH HHS · HL67307 · United States
NHLBI NIH HHS · HL68062 · United States
External Links
PubMed source DOI: 10.1016/j.febslet.2005.06.018 View journal details
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