Atrial fibrillation induces myocardial fibrosis through angiotensin II type 1 receptor-specific Arkadia-mediated downregulation of Smad7.
Atrial fibrillation induces myocardial fibrosis through angiotensin II type 1 receptor-specific Arkadia-mediated downregulation of Smad7.
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DOI：
10.1161/circresaha.110.234369
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发表时间：
2011-01-21
影响因子：
20.1
通讯作者：
Duan DD
中科院分区：
文献类型：
--
作者：
He X;Gao X;Peng L;Wang S;Zhu Y;Ma H;Lin J;Duan DD
心动过速诱发的心房纤维化是心房颤动（AF）结构重构的标志。房颤诱导心房纤维化的分子机制尚不清楚。探讨血管紧张素II（AngII）/AT 1受体偶联转化生长因子β1（TGF-β1）/Smads信号通路在房颤（AF）心房纤维化中的作用。用快速心房起搏（RAP，1000 ppm）于家兔左心房诱发心房颤动和纤维化。定量PCR和Western blot分析显示RAP可引起AngII、TGF-β1、磷酸化Smad 2/3（P-Smad 2/3）、Arkadia和羟脯氨酸合成的显著增加。TGF-β1/Smads介导的纤维化的关键内源性拮抗剂Smad 7的表达显著降低。这些变化可被AT 1受体拮抗剂氯沙坦剂量依赖性地逆转，提示AF诱导的AngII释放和AT 1受体特异性通路的激活参与了AF的作用。在成年兔心脏成纤维细胞中，AngII增加TGF-β1、P-Smad 2/3、Smad 4、Arkadia和I型胶原的表达，并显著降低Smad 7的表达。血管生成素II的这些作用可被氯沙坦逆转，但不能被AT 2拮抗剂（PD 123319）逆转。此外，细胞外信号调节激酶（ERK）抑制剂和抗TGF-β1抗体也可阻断AngII诱导的Smad 7下调。Smad 7基因沉默的siRNA废除氯沙坦的拮抗血管紧张素II的心脏成纤维细胞的纤维化作用，而Smad 7的过表达阻断血管紧张素II诱导的胶原I合成增加。AngII/AT 1受体特异性激活Arkadia介导的多聚泛素化和Smad 7降解可能降低TGF-β1/Smads信号的抑制性反馈调节，是AF诱导心房纤维化的重要机制。
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 (AngII)/AT1 receptor-coupled transforming growth factor β1 (TGF-β1)/Smads signaling pathway in the AF-induced atrial fibrosis. Rapid atrial pacing (RAP, 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 RAP caused a marked increase in the expression of AngII, TGF-β1, phosphorylated Smad2/3 (P-Smad2/3), Arkadia, and hydroxyproline synthesis. But the expression of Smad7, a key endogenous antagonist of the TGF-β1/Smads-mediated fibrosis, was significantly decreased. These changes were dose-dependently reversed by AT1 receptor antagonist losartan, implicating the involvement of AF-induced release of AngII and activation of AT1-receptor specific pathway. In the adult rabbit cardiac fibroblasts, AngII increased the expression of TGF-β1, P-Smad2/3, Smad4, Arkadia, and collagen I synthesis and significantly reduced Smad7 expression. These effects of AngII were reversed by losartan, but not by the AT2 antagonist (PD123319). In addition, extracellular signal-regulated kinase (ERK) inhibitor and anti-TGF-β1 antibody also blocked the AngII-induced downregulation of Smad7. Silencing of Smad7 gene by siRNA abolished losartan's antagonism on AngII's fibrogenic effects in cardiac fibroblasts while overexpression of Smad7 blocked AngII-induced increase in collagen I synthesis. AngII/AT1-receptor specific activation of Arkadia-mediated poly-ubiquitination and degradation of Smad7 may decrease the inhibitory feedback regulation of TGF-β1/Smads signaling and serves as a key mechanism for AF-induced atrial fibrosis.