Induction of TGF-β1 by high glucose or Ang-II, which then phosphorylates and activates downstream Smad2 and Smad3 proteins, results in cardiac fibrosis, cardiac hypertrophy and heart failure; however, Smad7 can antagonize TGF-β–mediated cardiac remodeling [18]. This evidence concerns the gene SMAD3 and cardiac hypertrophy.