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Laboratory and Animal Investigations |

Activation of the Calcineurin-Nuclear Factor of Activated T-Cell Signal Transduction Pathway in Atrial Fibrillation*

Chih-Chung Lin; Jiunn-Lee Lin, MD; Chich-Sheng Lin, PhD; Mei-Chuan Tsai; Ming-Jai Su, PhD; Ling-Ping Lai, MD, PhD; Shoei K. Stephen Huang, MD
Author and Funding Information

*From the Institute of Pharmacology (Mr. Lin, Ms. Tsai, and Drs. Su and Lai), National Taiwan University, Taipei; Department of Internal Medicine (Drs. J-L. Lin and Huang), National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei; and Department of Biological Science and Technology (Dr. C-S. Lin), National Chiao Tung University, Hsinchu, Taiwan.

Correspondence to: Ling-Ping Lai, MD, PhD, No. 1, Jen-Ai Rd, Section 1, Institute of Pharmacology, School of Medicine, National Taiwan University, Taipei, Taiwan, 100; e-mail: lai@ha.mc. ntu.edu.tw



Chest. 2004;126(6):1926-1932. doi:10.1378/chest.126.6.1926
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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 PO4 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.

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