TGF-β1 downregulates AT1 receptor expression via PKC-δ-mediated Sp1 dissociation from KLF4 and Smad-mediated PPAR-γ association with KLF4.
Cardiovascular effects of angiotensin II are primarily mediated via the angiotensin II type 1 receptor (AT1R). Krueppel-like factor 4 (KLF4), a transcription factor that binds to the transforming growth factor (TGF)-β control element (TCE), regulates a variety of receptor expression in vascular smooth muscle cells. In the present study, we ... investigated the mechanisms of TGF-β-mediated KLF4 regulation of AT1R expression.Coimmunoprecipitation, chromatin immunoprecipitation, and luciferase assays were performed, with the results suggesting that Sp1 forms a complex with KLF4 bound to the TCE of the AT1R promoter and cooperatively activates AT1R transcription in vascular smooth muscle cells under basal conditions. On activation of TGF-β1 signaling, Sp1 is dissociated from the KLF4-Sp1 complex through PKC-δ-mediated KLF4 phosphorylation at Thr401, downregulating AT1R expression. Simultaneously, TGF-β1 facilitates KLF4-PPAR-γ complex formation and its binding to the TCE of the AT1R promoter through Smad-mediated KLF4 phosphorylation at Ser470, subsequently leading to inhibition of AT1R transcription.KLF4 functions as a protein platform that is able to bind to the TCE of the AT1R promoter. On activation of TGF-β signaling, KLF4 mediates Sp1 dissociation from, and PPAR-γ association with, the AT1R promoter, leading to downregulation of AT1R expression in VSMCs.
Mesh Terms:
Animals, Binding Sites, Cell Proliferation, Chromatin Immunoprecipitation, Down-Regulation, Genes, Reporter, HEK293 Cells, Humans, Immunoprecipitation, Kruppel-Like Transcription Factors, Male, Muscle, Smooth, Vascular, Myocytes, Smooth Muscle, PPAR gamma, Phosphorylation, Promoter Regions, Genetic, Protein Kinase C-delta, RNA Interference, RNA, Messenger, Rats, Rats, Sprague-Dawley, Receptor, Angiotensin, Type 1, Serine, Smad Proteins, Sp1 Transcription Factor, Time Factors, Transcriptional Activation, Transfection, Transforming Growth Factor beta1
Animals, Binding Sites, Cell Proliferation, Chromatin Immunoprecipitation, Down-Regulation, Genes, Reporter, HEK293 Cells, Humans, Immunoprecipitation, Kruppel-Like Transcription Factors, Male, Muscle, Smooth, Vascular, Myocytes, Smooth Muscle, PPAR gamma, Phosphorylation, Promoter Regions, Genetic, Protein Kinase C-delta, RNA Interference, RNA, Messenger, Rats, Rats, Sprague-Dawley, Receptor, Angiotensin, Type 1, Serine, Smad Proteins, Sp1 Transcription Factor, Time Factors, Transcriptional Activation, Transfection, Transforming Growth Factor beta1
Arterioscler. Thromb. Vasc. Biol.
Date: Apr. 01, 2012
PubMed ID: 22282354
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