title: Integrated analysis of microRNA and mRNA expression profiles in the left atrium of patients with nonvalvular paroxysmal atrial fibrillation: Role of miR-146b-5p in atrial fibrosis.
abstract: BACKGROUND
  Studies have reported that the integrated analysis of microRNA (miRNA)-messenger RNA (mRNA) expression is valuable in exploring gene regulation systemically.
  
  
  OBJECTIVE
  The objectives of this study were to identify miRNAs and genes involved in atrial fibrillation and to explore the mechanisms underlying atrial fibrosis.
  
  
  METHODS
  We used microarrays to compare the differences in both miRNA and mRNA expression profiles in the left atrial appendage of patients with nonvalvular paroxysmal atrial fibrillation and healthy controls. Furthermore, the quantitative real-time polymerase chain reaction was used to confirm the reliability of the microarray data, prediction of the adopted databases, and Ingenuity Pathway Analysis of miRNA-mRNA expression in order to identify the miRNA target genes, examine the functions and pathways in which the target genes are involved, and construct an miRNA-target gene regulatory network. We further investigated the roles of miRNA-146b-5p in the mechanisms of atrial fibrosis.
  
  
  RESULTS
  We identified 10 differentially expressed miRNAs and 624 differentially expressed mRNAs, among which only 1 miRNA-target gene pair miR-146b-5p and tissue inhibitor of metalloproteinase 4 (TIMP-4) were constructed. The validated results revealed that miR-146b-5p, matrix metallopeptidase 9, and collagen content were upregulated whereas TIMP-4 was downregulated in patients with atrial fibrillation. After the transfection of miR-146b-5p into cardiac fibroblasts, TIMP-4 expression was markedly reduced and collagen content was increased. Moreover, luciferase results confirmed that TIMP-4 was a target of miR-146b-5p.
  
  
  CONCLUSIONS
  The identified miRNA and mRNA may represent a potentially novel molecular regulatory network, which may provide a better understanding of the molecular basis of remodeling in atrial fibrillation. miR-146b-5p probably acts as an intracellular mediator in the maladaptive remodeling in atrial fibrosis in atrial fibrillation.
authors.affiliation: Department of Cardiac Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing, People's Republic of China. Electronic address: wangjiangang7545@126.com.
authors.forename: Jiangang
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Pathology, Shantou University Medical College, Shantou, People's Republic of China. Electronic address: yywangut@163.com.
authors.forename: Yongyu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Cardiac Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing, People's Republic of China.
authors.forename: Jie
authors.initials: J
authors.lastname: Han
authors.affiliation: Department of Cardiac Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing, People's Republic of China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Internal Medicine, Vidant Medical Center, Broody School of Medicine, East Carolina University, Greenville, North Carolina.
authors.forename: Changqing
authors.initials: C
authors.lastname: Xie
authors.affiliation: Shanghai Cancer Center and Institutes of Biomedical Sciences, Fudan University, Shanghai, People's Republic of China.
authors.forename: Liqi
authors.initials: L
authors.lastname: Xie
authors.affiliation: Department of Cardiothoracic Surgery, Affiliated Hospital of Nantong University, Nantong, People's Republic of China.
authors.forename: Jiahai
authors.initials: J
authors.lastname: Shi
authors.affiliation: Center for Advanced Models for Translational Sciences and Therapeutics, University of Michigan Medical Center, Ann Arbor, Michigan.
authors.forename: Jifeng
authors.initials: J
authors.lastname: Zhang
authors.affiliation: University of Michigan Cardiovascular Center, University of Michigan, Ann Arbor, Michigan.
authors.forename: Bo
authors.initials: B
authors.lastname: Yang
authors.affiliation: Department of Pathology, Beijing Anzhen Hospital, Capital Medical University, Beijing, People's Republic of China.
authors.forename: Dong
authors.initials: D
authors.lastname: Chen
authors.affiliation: Department of Cardiac Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing, People's Republic of China.
authors.forename: Xu
authors.initials: X
authors.lastname: Meng
mesh_terms: D000328:Adult; D001281:Atrial Fibrillation / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D003094:Collagen / Q000235:genetics; D005260:Female; D005355:Fibrosis; D005786:Gene Expression Regulation; D006325:Heart Atria / Q000473:pathology*; D006801:Humans; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D015203:Reproducibility of Results; D019714:Tissue Inhibitor of Metalloproteinases / Q000235:genetics; D000097792:Tissue Inhibitor of Metalloproteinase-4
chemical_list: D003094:Collagen; D020780:Matrix Metalloproteinase 9; D035683:MicroRNAs; D019714:Tissue Inhibitor of Metalloproteinases; D000097792:Tissue Inhibitor of Metalloproteinase-4; C542542:MIRN146 microRNA, human; C579270:MMP9 protein, human
keywords: Atrial fibrillation; Fibrosis; MicroRNA; MicroRNA-146; Nonvalvular