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          Institute: MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut)     Collection: Yearbook_2014     Display Documents

ID: 682123.0, MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut) / Yearbook_2014
Transforming growth factor-beta-activated kinase 1 regulates angiogenesis via AMP-activated protein kinase-alpha1 and redox balance in endothelial cells
Authors:Zippel, N.; Malik, R. A.; Fromel, T.; Popp, R.; Bess, E.; Strilic, B.; Wettschureck, N.; Fleming, I.; Fisslthaler, B.
Date of Publication (YYYY-MM-DD):2013-12
Journal Abbrev.:Arterioscler Thromb Vasc Biol
Issue / Number:12
Start Page:2792
End Page:2799
Audience:Not Specified
Abstract / Description:OBJECTIVE: Transforming growth factor-beta-activated kinase 1 (TAK1) is a mitogen-activated protein 3-kinase and an AMP-activated protein kinase (AMPK) kinase in some cell types. Although TAK1(-/-) mice display defects in developmental vasculogenesis, the role of TAK1 in endothelial cells has not been investigated in detail. APPROACH AND RESULTS: TAK1 downregulation (small interfering RNA) in human endothelial cells attenuated proliferation without inducing apoptosis and diminished endothelial cell migration, as well as tube formation. Cytokine- and vascular endothelial growth factor (VEGF)-induced endothelial cell sprouting in a modified spheroid assay were abrogated by TAK1 downregulation. Moreover, VEGF-induced endothelial sprouting was impaired in aortic rings from mice lacking TAK1 in endothelial cells (TAK(DeltaEC)). TAK1 inhibition and downregulation also inhibited VEGF-stimulated phosphorylation of several kinases, including AMPK. Proteomic analyses revealed that superoxide dismutase 2 (SOD2) expression was reduced in TAK1-deficient endothelial cells, resulting in attenuated hydrogen peroxide production but increased mitochondrial superoxide production. Endothelial cell SOD2 expression was also attenuated by AMPK inhibition and in endothelial cells from AMPKalpha1(-/-) mice but was unaffected by inhibitors of c-Jun N-terminal kinase, p38, extracellular signal-regulated kinase 1/2, or phosphatidylinositol 3-kinase/Akt. Moreover, the impaired endothelial sprouting from TAK(DeltaEC) aortic rings was abrogated in the presence of polyethylene glycol-SOD, and tube formation was normalized by the overexpression of SOD2. A similar rescue of angiogenesis was observed in polyethylene glycol-SOD-treated aortic rings from mice with endothelial cell-specific deletion of the AMPKalpha1. CONCLUSIONS: These results establish TAK1 as an AMPKalpha1 kinase that regulates vascular endothelial growth factor-induced and cytokine-induced angiogenesis by modulating SOD2 expression and the superoxide anion:hydrogen peroxide balance.
Free Keywords:AMP-Activated Protein Kinases/antagonists &; inhibitors/deficiency/genetics/*metabolism; Animals; Antioxidants/pharmacology; Cell Movement; Cell Proliferation; Cells, Cultured; Endothelial Cells/drug effects/*enzymology; Human Umbilical Vein Endothelial Cells/enzymology; Humans; Hydrogen Peroxide/metabolism; Interleukin-1beta/metabolism; MAP Kinase Kinase Kinases/antagonists &; inhibitors/deficiency/genetics/*metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria/metabolism; Neovascularization, Physiologic; Oxidation-Reduction; Phosphorylation; Protein Kinase Inhibitors/pharmacology; RNA Interference; Receptors, LDL/genetics/metabolism; Signal Transduction; Superoxide Dismutase/genetics/metabolism; Time Factors; Transfection; Vascular Endothelial Growth Factor A/metabolism
External Publication Status:published
Document Type:Article
Communicated by:Svea Hümmer
Affiliations:MPI für physiologische und klinische Forschung
Identifiers:ISSN:1524-4636 (Electronic) 1079-5642 (Linking) %R 10.1161/ATVBAHA.113.301848
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