Abstract
The activation of transforming growth factor-β1(TGF-β1)/Smad signaling pathway and increased expression of connective tissue growth factor (CTGF) induced by angiotensin II (AngII) have been proposed as a mechanism for atrial fibrosis. However, whether TGFβ1/non-Smad signaling pathways involved in AngII-induced fibrogenetic factor expression remained unknown. Recently tumor necrosis factor receptor associated factor 6 (TRAF6)/TGFβ-associated kinase 1 (TAK1) has been shown to be crucial for the activation of TGF-β1/non-Smad signaling pathways. In the present study, we explored the role of TGF-β1/TRAF6 pathway in AngII-induced CTGF expression in cultured adult atrial fibroblasts. AngII (1 μM) provoked the activation of P38 mitogen activated protein kinase (P38 MAPK), extracellular signal-regulated kinase 1/2(ERK1/2) and c-Jun NH(2)-terminal kinase (JNK). AngII (1 μM) also promoted TGFβ1, TRAF6, CTGF expression and TAK1 phosphorylation, which were suppressed by angiotensin type I receptor antagonist (Losartan) as well as p38 MAPK inhibitor (SB202190), ERK1/2 inhibitor (PD98059) and JNK inhibitor (SP600125). Meanwhile, both TGFβ1 antibody and TRAF6 siRNA decreased the stimulatory effect of AngII on TRAF6, CTGF expression and TAK1 phosphorylation, which also attenuated AngII-induced atrial fibroblasts proliferation. In summary, the MAPKs/TGFβ1/TRAF6 pathway is an important signaling pathway in AngII-induced CTGF expression, and inhibition of TRAF6 may therefore represent a new target for reversing Ang II-induced atrial fibrosis.
Copyright © 2012 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Angiotensin II / pharmacology
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Angiotensin II / physiology*
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Animals
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Connective Tissue Growth Factor / genetics
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Connective Tissue Growth Factor / metabolism*
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Fibroblasts / drug effects
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Fibroblasts / metabolism*
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Fibroblasts / pathology
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Fibrosis / genetics
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Fibrosis / metabolism
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Gene Expression / drug effects
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Heart Atria / drug effects
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Heart Atria / metabolism
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Heart Atria / pathology
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Losartan / pharmacology
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MAP Kinase Kinase 4 / antagonists & inhibitors
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MAP Kinase Kinase 4 / genetics
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MAP Kinase Kinase 4 / metabolism
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MAP Kinase Kinase Kinases / antagonists & inhibitors
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MAP Kinase Kinase Kinases / genetics
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MAP Kinase Kinase Kinases / metabolism
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Mice
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Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 1 / genetics
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 3 / genetics
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Mitogen-Activated Protein Kinase 3 / metabolism
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Primary Cell Culture
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Protein Kinase Inhibitors / pharmacology
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Signal Transduction / drug effects
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Signal Transduction / genetics
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TNF Receptor-Associated Factor 6 / antagonists & inhibitors
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TNF Receptor-Associated Factor 6 / genetics*
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TNF Receptor-Associated Factor 6 / metabolism
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Transforming Growth Factor beta1 / antagonists & inhibitors
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Transforming Growth Factor beta1 / genetics*
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Transforming Growth Factor beta1 / metabolism
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
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p38 Mitogen-Activated Protein Kinases / genetics*
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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CCN2 protein, mouse
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Protein Kinase Inhibitors
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TNF Receptor-Associated Factor 6
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Transforming Growth Factor beta1
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Angiotensin II
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Connective Tissue Growth Factor
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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p38 Mitogen-Activated Protein Kinases
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MAP Kinase Kinase Kinases
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MAP kinase kinase kinase 7
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MAP Kinase Kinase 4
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Losartan