title: Activation of the calcineurin-nuclear factor of activated T-cell signal transduction pathway in atrial fibrillation.
abstract: OBJECTIVE
  The calcineurin-nuclear factor of activated T-cell (NFAT) signal transduction pathway regulates the expression of a plethora of genes in the myocardium. Cytosolic calcium overloading occurs in atrial fibrillation (AF), and this fulfills the condition needed for activation of this pathway. We therefore investigated the NFAT pathway in atrial tissue in a porcine model of AF.
  
  
  RESULTS
  AF was induced in eight adult pigs by rapid atrial pacing. Investigations on the calcineurin and NFAT pathway were performed on transmural left atrial tissue obtained 6 weeks after implantation of the pacemaker (pacing for 4 weeks, and AF without pacing for 2 weeks). In the AF group, the left atrial dimension increased significantly (26 +/- 4 mm vs 31 +/- 4 mm, respectively, p < 0.05 [mean +/- SD]). Calcineurin enzyme activity increased significantly in pigs with AF (n = 8) when compared to control pigs (n = 6) [0.143 +/- 0.034 vs 0.038 +/- 0.063 mmol PO(4)(-) released, p < 0.01]. We found that both NFAT-c3 and NFAT-c4, the downstream effectors of calcineurin, increased significantly in the nuclei in AF tissue using immunoblotting. Translocation of NFAT-c3 and NFAT-c4 into the nuclei was also demonstrated in AF tissue microsections using immunohistochemistry. The electrophoresis mobility shift assay further demonstrated that nuclear extracts from AF tissue had a significantly larger binding capacity for NFAT-specific oligonucleotide probes.
  
  
  CONCLUSIONS
  Our results demonstrate that calcineurin activity was increased in AF with subsequent NFAT-c3 and NFAT-c4 translocation into the nucleus. Activation of this signal transduction pathway may play an important role in the pathogenesis of AF.
authors.affiliation: Institute of Pharmacology, School of Medicine, National Taiwan University, No. 1 Jen-Ai Road Section 1, Taipei, Taiwan 100.
authors.forename: Chih-Chung
authors.initials: CC
authors.lastname: Lin
authors.forename: Jiunn-Lee
authors.initials: JL
authors.lastname: Lin
authors.forename: Chich-Sheng
authors.initials: CS
authors.lastname: Lin
authors.forename: Mei-Chuan
authors.initials: MC
authors.lastname: Tsai
authors.forename: Ming-Jai
authors.initials: MJ
authors.lastname: Su
authors.forename: Ling-Ping
authors.initials: LP
authors.lastname: Lai
authors.forename: Shoei K Stephen
authors.initials: SK
authors.lastname: Huang
mesh_terms: D000818:Animals; D001281:Atrial Fibrillation / Q000378:metabolism*; D019703:Calcineurin / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D024202:Electrophoretic Mobility Shift Assay; D006325:Heart Atria / Q000378:metabolism*; D007150:Immunohistochemistry; D008213:Lymphocyte Activation; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins / Q000378:metabolism*; D015398:Signal Transduction; D013552:Swine; D013601:T-Lymphocytes; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D014157:Transcription Factors; D019703:Calcineurin