Department of Cardiology, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
Circ Res. 2011 Jan 21;108(2):164-75. doi: 10.1161/CIRCRESAHA.110.234369. Epub 2010 Dec 2.
Tachycardia-induced atrial fibrosis is a hallmark of structural remodeling of atrial fibrillation (AF). The molecular mechanisms underlying the AF-induced atrial fibrosis remain unclear.
To determine the role of angiotensin II (Ang II)/Ang II type 1 (AT(1)) receptor-coupled transforming growth factor (TGF)-β(1)/Smad signaling pathway in the AF-induced atrial fibrosis.
Rapid atrial pacing (1000 ppm) was applied to the left atrium of rabbit heart to induce atrial fibrillation and fibrosis. Quantitative PCR and Western blot analysis revealed that rapid atrial pacing caused a marked increase in the expression of Ang II, TGF-β(1), phosphorylated Smad2/3 (P-Smad2/3), Arkadia, and hydroxyproline synthesis. However, the expression of Smad7, a key endogenous antagonist of the TGF-β(1)/Smad-mediated fibrosis, was significantly decreased. These changes were dose-dependently reversed by AT(1) receptor antagonist losartan, implicating the involvement of AF-induced release of Ang II and activation of AT(1) receptor-specific pathway. In the adult rabbit cardiac fibroblasts, Ang II increased the expression of TGF-β(1), P-Smad2/3, Smad4, Arkadia, and collagen I synthesis and significantly reduced Smad7 expression. These effects of Ang II were reversed by losartan but not by the AT(2) antagonist (PD123319). In addition, extracellular signal-regulated kinase inhibitor and anti-TGF-β(1) antibody also blocked the Ang II-induced downregulation of Smad7. Silencing of Smad7 gene by small interfering RNA abolished the antagonism of losartan on the fibrogenic effects of Ang II on cardiac fibroblasts, whereas overexpression of Smad7 blocked Ang II-induced increase in collagen I synthesis.
Ang II/AT(1) receptor-specific activation of Arkadia-mediated poly-ubiquitination and degradation of Smad7 may decrease the inhibitory feedback regulation of TGF-β(1)/Smad signaling and serves as a key mechanism for AF-induced atrial fibrosis.
心动过速诱导的心房纤维化是心房颤动（AF）结构重构的标志。AF 引起的心房纤维化的分子机制尚不清楚。
确定血管紧张素 II（Ang II）/Ang II 型 1（AT（1））受体偶联的转化生长因子（TGF）-β（1）/Smad 信号通路在 AF 诱导的心房纤维化中的作用。
快速心房起搏（1000ppm）应用于兔心左心房以诱导心房颤动和纤维化。定量 PCR 和 Western blot 分析显示，快速心房起搏导致 Ang II、TGF-β（1）、磷酸化 Smad2/3（P-Smad2/3）、Arkadia 和羟脯氨酸合成的表达显著增加。然而，TGF-β（1）/Smad 介导纤维化的关键内源性拮抗剂 Smad7 的表达明显降低。这些变化被 AT（1）受体拮抗剂洛沙坦剂量依赖性地逆转，表明 AF 诱导的 Ang II 释放和 AT（1）受体特异性途径的激活参与其中。在成年兔心脏成纤维细胞中，Ang II 增加了 TGF-β（1）、P-Smad2/3、Smad4、Arkadia 和胶原 I 合成的表达，并显著降低了 Smad7 的表达。这些 Ang II 的作用被洛沙坦逆转，但被 AT（2）拮抗剂（PD123319）逆转。此外，细胞外信号调节激酶抑制剂和抗 TGF-β（1）抗体也阻断了 Ang II 诱导的 Smad7 下调。通过小干扰 RNA 沉默 Smad7 基因消除了洛沙坦对 Ang II 对心脏成纤维细胞纤维生成作用的拮抗作用，而过表达 Smad7 则阻断了 Ang II 诱导的胶原 I 合成增加。
Ang II/AT（1）受体特异性激活 Arkadia 介导的多泛素化和 Smad7 的降解可能降低 TGF-β（1）/Smad 信号的抑制性反馈调节，是 AF 诱导的心房纤维化的关键机制。
