Activation of the calcineurin-nuclear factor of activated T-cell signal transduction pathway in atrial fibrillation.
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.
Lin
Chih-Chung
CC
Institute of Pharmacology, School of Medicine, National Taiwan University, No. 1 Jen-Ai Road Section 1, Taipei, Taiwan 100.
Lin
Jiunn-Lee
JL
Lin
Chich-Sheng
CS
Tsai
Mei-Chuan
MC
Su
Ming-Jai
MJ
Lai
Ling-Ping
LP
Huang
Shoei K Stephen
SK
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*
D004268:DNA-Binding Proteins; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D014157:Transcription Factors; D019703:Calcineurin