Smad2 Mediates Transforming Growth Factor-β Induction of Endothelial Nitric Oxide Synthase Expression

• Published in: Circulation research 2002-11, Vol.91 (9), p.806-813
• Main Authors: Saura, Marta, Zaragoza, Carlos, Cao, Wangsen, Bao, Clare, Rodríguez-Puyol, Manuel, Rodríguez-Puyol, Diego, Lowenstein, Charles J
• Format: Article
• Language: English
• Subjects: Active Transport, Cell Nucleus - drug effects; Active Transport, Cell Nucleus - physiology; Animals; Cattle; Cells, Cultured; DNA-Binding Proteins - antagonists & inhibitors; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Endothelium, Vascular - cytology; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Gene Expression Regulation - drug effects; Gene Expression Regulation - physiology; Humans; Ligases - biosynthesis; Ligases - genetics; Ligases - pharmacology; Nitric Oxide Synthase - biosynthesis; Nitric Oxide Synthase - genetics; Nitric Oxide Synthase Type III; Promoter Regions, Genetic - drug effects; Promoter Regions, Genetic - physiology; Protein Binding - drug effects; RNA, Messenger - metabolism; Signal Transduction - physiology; Smad2 Protein; Trans-Activators - antagonists & inhibitors; Trans-Activators - genetics; Trans-Activators - metabolism; Transcriptional Activation - drug effects; Transcriptional Activation - physiology; Transfection; Transforming Growth Factor beta - antagonists & inhibitors; Transforming Growth Factor beta - pharmacology; Ubiquitin-Protein Ligases
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/01.RES.0000040397.23817.E5

ABSTRACT—Transforming growth factor-β (TGF-β) increases expression of endothelial nitric oxide synthase (eNOS), although the precise mechanism by which it does so is unclear. We report that Smad2, a transcription factor activated by TGF-β, mediates TGF-β induction of eNOS in endothelial cells. TGF-β induces Smad2 translocation from cytoplasm to nucleus, where it directly interacts with a specific region of the eNOS promoter. Overexpression of Smad2 increases basal levels of eNOS, and further increases TGF-β stimulation of eNOS expression. Ectopic expression of Smurf, an antagonizer of Smad2, decreases Smad2 expression and blocks TGF-β induction of eNOS. Because Smad2 can interact with a variety of transcription factors, coactivators, and corepressors, Smad2 may thus act as an integrator of multiple signals in the regulation of eNOS expression.