Smad2 mediates transforming growth factor-beta induction of endothelial nitric oxide synthase expression

Circ Res. 2002 Nov 1;91(9):806-13. doi: 10.1161/01.res.0000040397.23817.e5.

Abstract

Transforming growth factor-beta (TGF-beta) 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-beta, mediates TGF-beta induction of eNOS in endothelial cells. TGF-beta 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-beta stimulation of eNOS expression. Ectopic expression of Smurf, an antagonizer of Smad2, decreases Smad2 expression and blocks TGF-beta 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 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

Substances

  • DNA-Binding Proteins
  • RNA, Messenger
  • SMAD2 protein, human
  • Smad2 Protein
  • Trans-Activators
  • Transforming Growth Factor beta
  • NOS3 protein, human
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type III
  • Ubiquitin-Protein Ligases
  • Ligases