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Heart Vessels. 2016 Oct;31(10):1696-708. doi: 10.1007/s00380-016-0808-z. Epub 2016 Mar 11.

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

Author information

1
Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial Key Laboratory of Coronary Disease, Guangdong General Hospital, Guangdong Academy of Medical Sciences, 106 Zhongshan Road 2, Guangzhou, 510080, China.
2
Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, 510060, China.
3
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, 510060, China.
4
Department of Radiation Oncology, Cancer Center, Sun Yat-sen University, Guangzhou, 510060, China.
5
Department of Cardiology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China.
6
Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial Key Laboratory of Coronary Disease, Guangdong General Hospital, Guangdong Academy of Medical Sciences, 106 Zhongshan Road 2, Guangzhou, 510080, China. chenjiyans@163.com.
7
Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial Key Laboratory of Coronary Disease, Guangdong General Hospital, Guangdong Academy of Medical Sciences, 106 Zhongshan Road 2, Guangzhou, 510080, China. zhouyinglingj@163.com.

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.

KEYWORDS:

Atrial fibrillation; Atrial fibrosis; MicroRNA-21; Smad7; Transforming growth factor-β1

PMID:
26968995
PMCID:
PMC5043001
DOI:
10.1007/s00380-016-0808-z
[Indexed for MEDLINE]
Free PMC Article

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