title: Signal Transducer and Activator of Transcription 3/MicroRNA-21 Feedback Loop Contributes to Atrial Fibrillation by Promoting Atrial Fibrosis in a Rat Sterile Pericarditis Model.
abstract: Postoperative atrial fibrillation is a frequent complication in cardiac surgery. The aberrant activation of signal transducer and activator of transcription 3 (STAT3) contributes to the pathogenesis of atrial fibrillation. MicroRNA-21 (miR-21) promotes atrial fibrosis. Recent studies support the existence of reciprocal regulation between STAT3 and miR-21. Here, we test the hypothesis that these 2 molecules might form a feedback loop that contributes to postoperative atrial fibrillation by promoting atrial fibrosis.
  
  
  
  A sterile pericarditis model was created using atrial surfaces dusted with sterile talcum powder in rats. The inflammatory cytokines interleukin (IL)-1β, IL-6, transforming growth factor-β, and tumor necrosis factor-α, along with STAT3 and miR-21, were highly upregulated in sterile pericarditis rats. The inhibition of STAT3 by S3I-201 resulted in miR-21 downregulation, which ameliorated atrial fibrosis and decreased the expression of the fibrosis-related genes, α-smooth muscle actin, collagen-1, and collagen-3; reduced the inhomogeneity of atrial conduction; and attenuated atrial fibrillation vulnerability. Meanwhile, treatment with antagomir-21 decreased STAT3 phosphorylation, alleviated atrial remodeling, abrogated sterile pericarditis-induced inhomogeneous conduction, and prevented atrial fibrillation promotion. The culturing of cardiac fibroblasts with IL-6 resulted in progressively augmented STAT3 phosphorylation and miR-21 levels. S3I-201 blocked IL-6 induced the expression of miR-21 and fibrosis-related genes in addition to cardiac fibroblast proliferation. Transfected antagomir-21 decreased the IL-6-induced cardiac fibroblast activation and STAT3 phosphorylation. The overexpression of miR-21 in cardiac fibroblasts caused the upregulation of STAT3 phosphorylation, enhanced fibrosis-related genes, and increased cell numbers.
  
  
  
  Our results have uncovered a novel reciprocal loop between STAT3 and miR-21 that is activated after heart surgery and can contribute to atrial fibrillation.
authors.affiliation: For the author affilations, please see the Appendix.
authors.forename: Zhengrong
authors.initials: Z
authors.lastname: Huang
authors.affiliation: For the author affilations, please see the Appendix.
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Chen
authors.affiliation: For the author affilations, please see the Appendix.
authors.forename: Cheng
authors.initials: C
authors.lastname: Qian
authors.affiliation: For the author affilations, please see the Appendix.
authors.forename: Qian
authors.initials: Q
authors.lastname: Dong
authors.affiliation: For the author affilations, please see the Appendix.
authors.forename: Dan
authors.initials: D
authors.lastname: Ding
authors.affiliation: For the author affilations, please see the Appendix.
authors.forename: Qiong-Feng
authors.initials: QF
authors.lastname: Wu
authors.affiliation: For the author affilations, please see the Appendix.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: For the author affilations, please see the Appendix.
authors.forename: Hong-Fei
authors.initials: HF
authors.lastname: Wang
authors.affiliation: For the author affilations, please see the Appendix.
authors.forename: Wei-Hua
authors.initials: WH
authors.lastname: Li
authors.affiliation: For the author affilations, please see the Appendix.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Xie
authors.affiliation: For the author affilations, please see the Appendix.
authors.forename: Xiang
authors.initials: X
authors.lastname: Cheng
authors.affiliation: For the author affilations, please see the Appendix. yimeidu@mail.hust.edu.cn zhaoning19870403@126.com.
authors.forename: Ning
authors.initials: N
authors.lastname: Zhao
authors.affiliation: For the author affilations, please see the Appendix. yimeidu@mail.hust.edu.cn zhaoning19870403@126.com.
authors.forename: Yi-Mei
authors.initials: YM
authors.lastname: Du
authors.affiliation: For the author affilations, please see the Appendix.
authors.forename: Yu-Hua
authors.initials: YH
authors.lastname: Liao
mesh_terms: D000818:Animals; D001281:Atrial Fibrillation / Q000378:metabolism* / Q000503:physiopathology* / Q000601:surgery; D004195:Disease Models, Animal; D005355:Fibrosis / Q000378:metabolism / Q000503:physiopathology; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D035683:MicroRNAs / Q000378:metabolism*; D010493:Pericarditis / Q000503:physiopathology; D010766:Phosphorylation; D051381:Rats; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D053583:Interleukin-1beta; D015850:Interleukin-6; D035683:MicroRNAs; D050796:STAT3 Transcription Factor; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha
keywords: arrhythmia; atrial fibrillation; microRNA; signal transduction