Activation of the calcineurin-nuclear factor of activated T-cell signal transduction pathway in atrial fibrillation

Chih Chung Lin, Jiunn Lee Lin, Chich Sheng Lin, Mei Chuan Tsai, Ming Jai Su, Ling Ping Lai, Shoei K. Stephen Huang

Research output: Contribution to journalArticlepeer-review

36 Citations (Scopus)

Abstract

Study objectives: 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. Methods and 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.

Original languageEnglish
Pages (from-to)1926-1932
Number of pages7
JournalChest
Volume126
Issue number6
DOIs
Publication statusPublished - Jan 1 2004
Externally publishedYes

Keywords

  • Atrial fibrillation
  • Calcineurin
  • Calcium
  • Nuclear factor of activated T cell

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine
  • Cardiology and Cardiovascular Medicine

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