Sodium Tanshinone IIA Sulfonate Prevents Angiotensin II‐Induced Differentiation of Human Atrial Fibroblasts into Myofibroblasts

Differentiation of atrial fibroblasts into myofibroblasts plays a critical role in atrial fibrosis. Sodium tanshinone IIA sulfonate (DS‐201), a water‐soluble derivative of tanshinone IIA, has been shown to have potent antifibrotic properties. However, the protective effects of DS‐201 on angiotensin II‐ (Ang II‐) induced differentiation of atrial fibroblasts into myofibroblasts remain to be elucidated. In this study, human atrial fibroblasts were stimulated with Ang II in the presence or absence of DS‐201. Then, α‐smooth muscle actin (α‐SMA), collagen I, and collagen III expression and reactive oxygen species (ROS) generation were measured. The expression of transforming growth factor‐β1 (TGF‐β1) and the downstream signaling of TGF‐β1, such as phosphorylation of Smad2/3, were also determined. The results demonstrated that DS‐201 significantly prevented Ang II‐induced human atrial fibroblast migration and decreased Ang II‐induced α‐SMA, collagen I, and collagen III expression. Furthermore, increased production of ROS and expression of TGF‐β1 stimulated by Ang II were also significantly inhibited by DS‐201. Consistent with these results, DS‐201 significantly inhibited Ang II‐evoked Smad2/3 phosphorylation and periostin expression. These results and the experiments involving N‐acetyl cysteine (antioxidant) and an anti‐TGF‐β1 antibody suggest that DS‐201 prevent Ang II‐induced differentiation of atrial fibroblasts to myofibroblasts, at least in part, through suppressing oxidative stress and inhibiting the activation of TGF‐β1 signaling pathway. All of these data indicate the potential utility of DS‐201 for the treatment of cardiac fibrosis.