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

Abstract

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 AT1 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‐β1, phosphorylated Smad2/3 and Arkadia, it decreased Smad7 expression. These changes were reversed by AT1 receptor antagonist losartan in a dose‐dependent manner. Similar results were obtained in the adult rabbit cardiac fibroblast. In the presence of AngII, AT1 antagonist, but not the AT2 antagonist PD123319, restored Smad7 expression and caused a decrease in P‐Smad2/3, Smad4 collagen I and Arkadia, indicating a key role of AT1 receptor‐specific inhibition of Smad7 in the AngII‐induced fibrosis and suggesting that AT1 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‐β1 reversed the AngII‐induced inhibition of Smad7 expression. Thus, AngII may induce atrial fibrosis through an AT1‐receptor specific activation of TGF‐β1, which in turn decreases the inhibitory Smad7 and increases P‐Smad2/3. These results suggest a key role of AT1 receptor specific inhibition of Smad7 in AF‐induced atrial fibrosis. (Supported by Guangdong SFC #06021342 and NCRR P‐20 RR‐15581)