title: Rapid atrial pacing induces myocardial fibrosis by down-regulating Smad7 via microRNA-21 in rabbit.
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.
authors.affiliation: 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.
authors.forename: Xuyu
authors.initials: X
authors.lastname: He
authors.affiliation: Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, 510060, China.|State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, 510060, China.|Department of Radiation Oncology, Cancer Center, Sun Yat-sen University, Guangzhou, 510060, China.
authors.forename: Kunyi
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China.
authors.forename: Xiuren
authors.initials: X
authors.lastname: Gao
authors.affiliation: 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.
authors.forename: Liwen
authors.initials: L
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Hong
authors.initials: H
authors.lastname: Tan
authors.affiliation: 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.
authors.forename: Jiyan
authors.initials: J
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Yingling
authors.initials: Y
authors.lastname: Zhou
mesh_terms: D000818:Animals; D001281:Atrial Fibrillation / Q000235:genetics / Q000378:metabolism*; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D005347:Fibroblasts / Q000187:drug effects*; D005355:Fibrosis; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D051906:Smad7 Protein / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D035683:MicroRNAs; D051906:Smad7 Protein; C497808:Smad7 protein, rat; D053773:Transforming Growth Factor beta1; C546082:mirn21 microRNA, rat; D003094:Collagen
keywords: Atrial fibrillation; Atrial fibrosis; MicroRNA-21; Smad7; Transforming growth factor-β1