TGF- 1 Downregulates AT1 Receptor Expression via PKC- -Mediated Sp1 Dissociation From KLF4 and Smad-Mediated PPAR- Association With KLF4

X.-h. Zhang, B. Zheng, C. Gu, J.-r. Fu, J.-k. Wen
2012 Arteriosclerosis, Thrombosis and Vascular Biology  
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)-␤ control element (TCE), regulates a variety of receptor expression in vascular smooth muscle cells. In the present study, we investigated the mechanisms of TGF-␤-mediated KLF4 regulation of AT1R expression. Methods and Results-Coimmunoprecipitation, chromatin
more » ... ation, 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-␤1 signaling, Sp1 is dissociated from the KLF4-Sp1 complex through PKC-␦-mediated KLF4 phosphorylation at Thr401, downregulating AT1R expression. Simultaneously, TGF-␤1 facilitates KLF4-PPAR-␥ 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-␤ signaling, KLF4 mediates Sp1 dissociation from, and PPAR-␥ association with, the AT1R promoter, leading to downregulation of AT1R expression in VSMCs. (Arterioscler Thromb Vasc Biol. 2012;32:1015-1023.)
doi:10.1161/atvbaha.111.244962 pmid:22282354 fatcat:okqrvv3dbbew3koap6rhdt5lom