AT1 Receptor‐specific down‐regulation of Smad7 Plays a Key Role in Atrial Fibrillation‐Induced Myocardial Fibrosis

Tachycardia‐induced atrial fibrosis is a hallmark for structural remodeling of atrial fibrillation (AF). But the molecular mechanisms for the genesis of atrial fibrosis remain unclear. In this study, we tested whether AT 1 receptor‐specific inhibition of Smad7 plays a key role in the AF‐induced atrial fibrosis. Atrial fibrillation and fibrosis was induced by rapid atrial pacing (RAP, 1000 ppm) to the left atrium of rabbit heart. While RAP caused a significant increase in the expression of AngII, hydroxyproline, TGF‐β 1 , phosphorylated Smad2/3 and Arkadia, it decreased Smad7 expression. These changes were reversed by AT 1 receptor antagonist losartan in a dose‐dependent manner. Similar results were obtained in the adult rabbit cardiac fibroblast. In the presence of AngII, AT 1 antagonist, but not the AT 2 antagonist PD123319, restored Smad7 expression and caused a decrease in P‐Smad2/3, Smad4 collagen I and Arkadia, indicating a key role of AT 1 receptor‐specific inhibition of Smad7 in the AngII‐induced fibrosis and suggesting that AT 1 receptor‐specific inhibition of Smad7 may be mediated by Arkadia‐induced Smad7 poly‐ubiquitination and degradation. In addition, interruption of both ERK mitogen‐activated protein kinase (MAPK) and TGF‐β 1 reversed the AngII‐induced inhibition of Smad7 expression. Thus, AngII may induce atrial fibrosis through an AT 1 ‐receptor specific activation of TGF‐β 1 , which in turn decreases the inhibitory Smad7 and increases P‐Smad2/3. These results suggest a key role of AT 1 receptor specific inhibition of Smad7 in AF‐induced atrial fibrosis. (Supported by Guangdong SFC #06021342 and NCRR P‐20 RR‐15581)