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 journalArticle

35 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

Fingerprint

NFATC Transcription Factors
Calcineurin
Atrial Fibrillation
Signal Transduction
Swine
Oligonucleotide Probes
Electrophoretic Mobility Shift Assay
Immunoblotting
Electrophoresis
Myocardium
Immunohistochemistry

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

Cite this

Activation of the calcineurin-nuclear factor of activated T-cell signal transduction pathway in atrial fibrillation. / Lin, Chih Chung; Lin, Jiunn Lee; Lin, Chich Sheng; Tsai, Mei Chuan; Su, Ming Jai; Lai, Ling Ping; Stephen Huang, Shoei K.

In: Chest, Vol. 126, No. 6, 01.01.2004, p. 1926-1932.

Research output: Contribution to journalArticle

Lin, Chih Chung ; Lin, Jiunn Lee ; Lin, Chich Sheng ; Tsai, Mei Chuan ; Su, Ming Jai ; Lai, Ling Ping ; Stephen Huang, Shoei K. / Activation of the calcineurin-nuclear factor of activated T-cell signal transduction pathway in atrial fibrillation. In: Chest. 2004 ; Vol. 126, No. 6. pp. 1926-1932.
@article{49d4cf957c78410aaa38fb7b45f4f4f0,
title = "Activation of the calcineurin-nuclear factor of activated T-cell signal transduction pathway in atrial fibrillation",
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.",
keywords = "Atrial fibrillation, Calcineurin, Calcium, Nuclear factor of activated T cell, Atrial fibrillation, Calcineurin, Calcium, Nuclear factor of activated T cell",
author = "Lin, {Chih Chung} and Lin, {Jiunn Lee} and Lin, {Chich Sheng} and Tsai, {Mei Chuan} and Su, {Ming Jai} and Lai, {Ling Ping} and {Stephen Huang}, {Shoei K.}",
year = "2004",
month = "1",
day = "1",
doi = "10.1378/chest.126.6.1926",
language = "English",
volume = "126",
pages = "1926--1932",
journal = "Chest",
issn = "0012-3692",
publisher = "American College of Chest Physicians",
number = "6",

}

TY - JOUR

T1 - Activation of the calcineurin-nuclear factor of activated T-cell signal transduction pathway in atrial fibrillation

AU - Lin, Chih Chung

AU - Lin, Jiunn Lee

AU - Lin, Chich Sheng

AU - Tsai, Mei Chuan

AU - Su, Ming Jai

AU - Lai, Ling Ping

AU - Stephen Huang, Shoei K.

PY - 2004/1/1

Y1 - 2004/1/1

N2 - 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.

AB - 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.

KW - Atrial fibrillation

KW - Calcineurin

KW - Calcium

KW - Nuclear factor of activated T cell

KW - Atrial fibrillation

KW - Calcineurin

KW - Calcium

KW - Nuclear factor of activated T cell

UR - http://www.scopus.com/inward/record.url?scp=10444288776&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=10444288776&partnerID=8YFLogxK

U2 - 10.1378/chest.126.6.1926

DO - 10.1378/chest.126.6.1926

M3 - Article

VL - 126

SP - 1926

EP - 1932

JO - Chest

JF - Chest

SN - 0012-3692

IS - 6

ER -