Abstract
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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00380-016-0808-z) contains supplementary material, which is available to authorized users.
Highlights
Atrial fibrillation (AF) is one of the most common cardiac arrhythmias and remains a major contributor to morbidity and mortality in clinical practice [1, 2]
We previously reported that the high expression of transforming growth factor-β1 (TGF-β1) in pathological conditions could cause the downregulation of Smad7, which contributes to the development of myocardial fibrosis in AF [10]
The expression of the inhibitory Smad, Smad7, was significantly lower in the rapid atrial pacing (RAP) group (Fig. 1e, f). This finding further confirmed that TGF-β1/Smad7 was involved in RAPinduced myocardial remodeling
Summary
Atrial fibrillation (AF) is one of the most common cardiac arrhythmias and remains a major contributor to morbidity and mortality in clinical practice [1, 2]. Activated TGF-β1 binds to membrane-bound heteromeric receptor kinases (TβRI and TβRII) that transduce intracellular signals via both Smad and non-Smad pathways. Activated TβRI and TβRII receptors phosphorylate receptor regulated Smads (R-Smads, such as Smad2/3), which form homomeric complexes and heteromeric complexes with a co-Smad (Smad4) [8, 9, 12]. These activated Smad complexes translocate into the nucleus, where they accumulate and bind to target genes to directly regulate their transcription and the production of related proteins such as fibrin [5, 8]. We previously reported that the high expression of TGF-β1 in pathological conditions could cause the downregulation of Smad, which contributes to the development of myocardial fibrosis in AF [10]. The molecular mechanism of the regulation of Smad expression through TGF-β1 remains unclear in AF
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