TGF-β1 Downregulates AT1 Receptor Expression via PKC-δ-Mediated Sp1 Dissociation From KLF4 and Smad-Mediated PPAR-γ Association With KLF4
OBJECTIVE—Cardiovascular effects of angiotensin II are primarily mediated via the angiotensin II type 1 receptor (AT1R). Krüppel-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 vasc...
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Veröffentlicht in: | Arteriosclerosis, thrombosis, and vascular biology thrombosis, and vascular biology, 2012-04, Vol.32 (4), p.1015-1023 |
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Zusammenfassung: | OBJECTIVE—Cardiovascular effects of angiotensin II are primarily mediated via the angiotensin II type 1 receptor (AT1R). Krüppel-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.
METHODS AND RESULTS—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.
CONCLUSION—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. |
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ISSN: | 1079-5642 1524-4636 |
DOI: | 10.1161/ATVBAHA.111.244962 |