title: Angiotensin II increases CTGF expression via MAPKs/TGF-β1/TRAF6 pathway in atrial fibroblasts.
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.
authors: Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China.
authors: Jun
authors: J
authors: Gu
authors: Xu
authors: X
authors: Liu
authors: Quan-xing
authors: QX
authors: Wang
authors: Hong-wei
authors: HW
authors: Tan
authors: Meng
authors: M
authors: Guo
authors: Wei-feng
authors: WF
authors: Jiang
authors: Li
authors: L
authors: Zhou
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology / Q000502:physiology*; D000818:Animals; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005355:Fibrosis / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006325:Heart Atria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019808:Losartan / Q000494:pharmacology; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D061251:Primary Cell Culture; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D048029:TNF Receptor-Associated Factor 6 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D000804:Angiotensin II; D055513:Connective Tissue Growth Factor; D019808:Losartan; D048670:MAP Kinase Kinase 4; D020930:MAP Kinase Kinase Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D047428:Protein Kinase Inhibitors; D048029:TNF Receptor-Associated Factor 6; D053773:Transforming Growth Factor beta1; D048051:p38 Mitogen-Activated Protein Kinases; D000099151:MAP Kinase Kinase Kinase 7; C526318:CCN2 protein, mouse