Rapid atrial pacing induces myocardial fibrosis by down-regulating Smad7 via microRNA-21 in rabbit

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• 作者：Xuyu He ; Kunyi Zhang ; Xiuren Gao ; Liwen Li ; Hong Tan ; Jiyan Chen…
• 关键词：Atrial fibrosis ; Atrial fibrillation ; Smad7 ; MicroRNA ; 21 ; Transforming growth factor ; β1
• 刊名：Heart and Vessels
• 出版年：2016
• 出版时间：October 2016
• 年：2016
• 卷：31
• 期：10
• 页码：1696-1708
• 全文大小：1,214 KB
• 刊物类别：Medicine
• 刊物主题：Medicine & Public Health
  Cardiology
  Cardiac Surgery
  Vascular Surgery
  Biomedical Engineering
  Interventional Radiology
  Ultrasound
  
• 出版者：Springer Japan
• ISSN：1615-2573
• 卷排序：31

文摘

Tachycardia-induced atrial fibrosis is a hallmark of the structural remodeling of atrial fibrillation (AF). The mechanisms underlying tachycardia-induced atrial fibrosis remain unclear. In our previous study, we found that Smad7-downregulation promoted the development of atrial fibrosis in AF. Fibroblasts are enriched in microRNA-21 (miR-21), which contributes to the development of fibrosis and heart failure in the cardiovascular system. Our study was designed to test the hypothesis that miR-21 reinforces the TGF-β₁/Smad signaling pathway in AF-induced atrial fibrosis by down-regulating Smad7. Rapid atrial pacing (RAP, 1000 ppm) was applied to the left atrium of the rabbit heart to induce atrial fibrillation and fibrosis. qRT-PCR and northern blot analysis revealed that RAP caused a marked increase in the expression of miR-21. Transfection with a miR-21 inhibitor significantly increased the expression of Smad7, while the expression of collagen I/III significantly decreased. These changes were implicated in the AF-induced release of miR-21 and down-regulation of Smad7. Adult rat cardiac fibroblasts treated with TGF-β₁ showed increased miR-21 expression and decreased Smad7 expression. Pretreatment with a TGF-β₁ inhibitor reduced the TGF-β₁-induced up-regulation of miR-21. Pretreatment with pre-miR-21 and a miR-21 inhibitor significantly decreased and increased Smad7 expression, respectively. This result was negatively correlated with the expression of collagen I/III in fibroblasts. Moreover, the results of a luciferase activity assay suggest that Smad7 is a validated miR-21 target in CFs. Our results provide compelling evidence that the miR-21 specific degradation of Smad7 may decrease the inhibitory feedback regulation of TGF-β1/Smad signaling and serves as a new insight of the mechanism of atrial fibrosis in atrial fibrillation.