Cellular signaling underlying atrial tachycardia remodeling of L-type calcium current

Xiao Yan Qi, Yung-Hsin Yeh, Ling Xiao, Brett Burstein, Ange Maguy, Denis Chartier, Louis R Villeneuve, Bianca J J M Brundel, Dobromir Dobrev, Stanley Nattel

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Atrial tachycardia (AT) downregulates L-type Ca(2+) current (I(CaL)) and causes atrial fibrillation-promoting electric remodeling. This study assessed potential underlying signal transduction. Cultured adult canine atrial cardiomyocytes were paced at 0, 1, or 3 Hz (P0, P1, P3) for up to 24 hours. Cellular tachypacing (P3) mimicked effects of in vivo AT: decreased I(CaL) and transient outward current (I(to)), unchanged I(CaT), I(Kr), and I(Ks), and reduced action potential duration (APD). I(CaL) was unchanged in P3 at 2 and 8 hours but decreased by 55+/-6% at 24 hours. Tachypacing caused Ca(2+)(i) accumulation in P3 cells at 2 to 8 hours, but, by 24 hours, Ca(2+)i returned to baseline. Ca(v)1.2 mRNA expression was not altered at 2 hours but decreased significantly at 8 and 24 hours (32+/-4% and 48+/-4%, respectively) and protein expression was decreased (47+/-8%) at 24 hours only. Suppressing Ca(2+)(i) increases during tachypacing with the I(CaL) blocker nimodipine or the Ca(2+) chelator BAPTA-AM prevented I(CaL) downregulation. Calcineurin activity increased in P3 at 2 and 8 hours, respectively, returning to baseline at 24 hours. Nuclear factor of activated T cells (NFAT) nuclear translocation was enhanced in P3 cells. Ca(2+)-dependent signaling was probed with inhibitors of Ca(2+)/calmodulin (W-7), calcineurin (FK-506), and NFAT (INCA6): each prevented I(CaL) downregulation. Significant APD reductions ( approximately 30%) at 24 hours in P3 cells were prevented by nimodipine, BAPTA-AM, W-7, or FK-506. Thus, rapid atrial cardiomyocyte activation causes Ca(2+) loading, which activates the Ca(2+)-dependent calmodulin-calcineurin-NFAT system to cause transcriptional downregulation of I(CaL), restoring Ca(2+)i to normal at the cost of APD reduction. These studies elucidate for the first time the molecular feedback mechanisms underlying arrhythmogenic AT remodeling.

Original languageEnglish
Pages (from-to)845-54
Number of pages10
JournalCirculation Research
Volume103
Issue number8
DOIs
Publication statusPublished - 10 Oct 2008

Cite this

Qi, X. Y., Yeh, Y-H., Xiao, L., Burstein, B., Maguy, A., Chartier, D., ... Nattel, S. (2008). Cellular signaling underlying atrial tachycardia remodeling of L-type calcium current. Circulation Research, 103(8), 845-54. https://doi.org/10.1161/CIRCRESAHA.108.175463
Qi, Xiao Yan ; Yeh, Yung-Hsin ; Xiao, Ling ; Burstein, Brett ; Maguy, Ange ; Chartier, Denis ; Villeneuve, Louis R ; Brundel, Bianca J J M ; Dobrev, Dobromir ; Nattel, Stanley. / Cellular signaling underlying atrial tachycardia remodeling of L-type calcium current. In: Circulation Research. 2008 ; Vol. 103, No. 8. pp. 845-54.
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abstract = "Atrial tachycardia (AT) downregulates L-type Ca(2+) current (I(CaL)) and causes atrial fibrillation-promoting electric remodeling. This study assessed potential underlying signal transduction. Cultured adult canine atrial cardiomyocytes were paced at 0, 1, or 3 Hz (P0, P1, P3) for up to 24 hours. Cellular tachypacing (P3) mimicked effects of in vivo AT: decreased I(CaL) and transient outward current (I(to)), unchanged I(CaT), I(Kr), and I(Ks), and reduced action potential duration (APD). I(CaL) was unchanged in P3 at 2 and 8 hours but decreased by 55+/-6{\%} at 24 hours. Tachypacing caused Ca(2+)(i) accumulation in P3 cells at 2 to 8 hours, but, by 24 hours, Ca(2+)i returned to baseline. Ca(v)1.2 mRNA expression was not altered at 2 hours but decreased significantly at 8 and 24 hours (32+/-4{\%} and 48+/-4{\%}, respectively) and protein expression was decreased (47+/-8{\%}) at 24 hours only. Suppressing Ca(2+)(i) increases during tachypacing with the I(CaL) blocker nimodipine or the Ca(2+) chelator BAPTA-AM prevented I(CaL) downregulation. Calcineurin activity increased in P3 at 2 and 8 hours, respectively, returning to baseline at 24 hours. Nuclear factor of activated T cells (NFAT) nuclear translocation was enhanced in P3 cells. Ca(2+)-dependent signaling was probed with inhibitors of Ca(2+)/calmodulin (W-7), calcineurin (FK-506), and NFAT (INCA6): each prevented I(CaL) downregulation. Significant APD reductions ( approximately 30{\%}) at 24 hours in P3 cells were prevented by nimodipine, BAPTA-AM, W-7, or FK-506. Thus, rapid atrial cardiomyocyte activation causes Ca(2+) loading, which activates the Ca(2+)-dependent calmodulin-calcineurin-NFAT system to cause transcriptional downregulation of I(CaL), restoring Ca(2+)i to normal at the cost of APD reduction. These studies elucidate for the first time the molecular feedback mechanisms underlying arrhythmogenic AT remodeling.",
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author = "Qi, {Xiao Yan} and Yung-Hsin Yeh and Ling Xiao and Brett Burstein and Ange Maguy and Denis Chartier and Villeneuve, {Louis R} and Brundel, {Bianca J J M} and Dobromir Dobrev and Stanley Nattel",
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Qi, XY, Yeh, Y-H, Xiao, L, Burstein, B, Maguy, A, Chartier, D, Villeneuve, LR, Brundel, BJJM, Dobrev, D & Nattel, S 2008, 'Cellular signaling underlying atrial tachycardia remodeling of L-type calcium current' Circulation Research, vol. 103, no. 8, pp. 845-54. https://doi.org/10.1161/CIRCRESAHA.108.175463

Cellular signaling underlying atrial tachycardia remodeling of L-type calcium current. / Qi, Xiao Yan; Yeh, Yung-Hsin; Xiao, Ling; Burstein, Brett; Maguy, Ange; Chartier, Denis; Villeneuve, Louis R; Brundel, Bianca J J M; Dobrev, Dobromir; Nattel, Stanley.

In: Circulation Research, Vol. 103, No. 8, 10.10.2008, p. 845-54.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Cellular signaling underlying atrial tachycardia remodeling of L-type calcium current

AU - Qi, Xiao Yan

AU - Yeh, Yung-Hsin

AU - Xiao, Ling

AU - Burstein, Brett

AU - Maguy, Ange

AU - Chartier, Denis

AU - Villeneuve, Louis R

AU - Brundel, Bianca J J M

AU - Dobrev, Dobromir

AU - Nattel, Stanley

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N2 - Atrial tachycardia (AT) downregulates L-type Ca(2+) current (I(CaL)) and causes atrial fibrillation-promoting electric remodeling. This study assessed potential underlying signal transduction. Cultured adult canine atrial cardiomyocytes were paced at 0, 1, or 3 Hz (P0, P1, P3) for up to 24 hours. Cellular tachypacing (P3) mimicked effects of in vivo AT: decreased I(CaL) and transient outward current (I(to)), unchanged I(CaT), I(Kr), and I(Ks), and reduced action potential duration (APD). I(CaL) was unchanged in P3 at 2 and 8 hours but decreased by 55+/-6% at 24 hours. Tachypacing caused Ca(2+)(i) accumulation in P3 cells at 2 to 8 hours, but, by 24 hours, Ca(2+)i returned to baseline. Ca(v)1.2 mRNA expression was not altered at 2 hours but decreased significantly at 8 and 24 hours (32+/-4% and 48+/-4%, respectively) and protein expression was decreased (47+/-8%) at 24 hours only. Suppressing Ca(2+)(i) increases during tachypacing with the I(CaL) blocker nimodipine or the Ca(2+) chelator BAPTA-AM prevented I(CaL) downregulation. Calcineurin activity increased in P3 at 2 and 8 hours, respectively, returning to baseline at 24 hours. Nuclear factor of activated T cells (NFAT) nuclear translocation was enhanced in P3 cells. Ca(2+)-dependent signaling was probed with inhibitors of Ca(2+)/calmodulin (W-7), calcineurin (FK-506), and NFAT (INCA6): each prevented I(CaL) downregulation. Significant APD reductions ( approximately 30%) at 24 hours in P3 cells were prevented by nimodipine, BAPTA-AM, W-7, or FK-506. Thus, rapid atrial cardiomyocyte activation causes Ca(2+) loading, which activates the Ca(2+)-dependent calmodulin-calcineurin-NFAT system to cause transcriptional downregulation of I(CaL), restoring Ca(2+)i to normal at the cost of APD reduction. These studies elucidate for the first time the molecular feedback mechanisms underlying arrhythmogenic AT remodeling.

AB - Atrial tachycardia (AT) downregulates L-type Ca(2+) current (I(CaL)) and causes atrial fibrillation-promoting electric remodeling. This study assessed potential underlying signal transduction. Cultured adult canine atrial cardiomyocytes were paced at 0, 1, or 3 Hz (P0, P1, P3) for up to 24 hours. Cellular tachypacing (P3) mimicked effects of in vivo AT: decreased I(CaL) and transient outward current (I(to)), unchanged I(CaT), I(Kr), and I(Ks), and reduced action potential duration (APD). I(CaL) was unchanged in P3 at 2 and 8 hours but decreased by 55+/-6% at 24 hours. Tachypacing caused Ca(2+)(i) accumulation in P3 cells at 2 to 8 hours, but, by 24 hours, Ca(2+)i returned to baseline. Ca(v)1.2 mRNA expression was not altered at 2 hours but decreased significantly at 8 and 24 hours (32+/-4% and 48+/-4%, respectively) and protein expression was decreased (47+/-8%) at 24 hours only. Suppressing Ca(2+)(i) increases during tachypacing with the I(CaL) blocker nimodipine or the Ca(2+) chelator BAPTA-AM prevented I(CaL) downregulation. Calcineurin activity increased in P3 at 2 and 8 hours, respectively, returning to baseline at 24 hours. Nuclear factor of activated T cells (NFAT) nuclear translocation was enhanced in P3 cells. Ca(2+)-dependent signaling was probed with inhibitors of Ca(2+)/calmodulin (W-7), calcineurin (FK-506), and NFAT (INCA6): each prevented I(CaL) downregulation. Significant APD reductions ( approximately 30%) at 24 hours in P3 cells were prevented by nimodipine, BAPTA-AM, W-7, or FK-506. Thus, rapid atrial cardiomyocyte activation causes Ca(2+) loading, which activates the Ca(2+)-dependent calmodulin-calcineurin-NFAT system to cause transcriptional downregulation of I(CaL), restoring Ca(2+)i to normal at the cost of APD reduction. These studies elucidate for the first time the molecular feedback mechanisms underlying arrhythmogenic AT remodeling.

KW - Action Potentials

KW - Animals

KW - Calcineurin/metabolism

KW - Calcium Channel Blockers/pharmacology

KW - Calcium Channels, L-Type/drug effects

KW - Calcium Signaling/drug effects

KW - Calmodulin/antagonists & inhibitors

KW - Cardiac Pacing, Artificial

KW - Cells, Cultured

KW - Chelating Agents/pharmacology

KW - Dogs

KW - Egtazic Acid/analogs & derivatives

KW - Heart Atria/metabolism

KW - Myocytes, Cardiac/drug effects

KW - NFATC Transcription Factors/metabolism

KW - Nimodipine/pharmacology

KW - Potassium/metabolism

KW - RNA, Messenger/metabolism

KW - Sulfonamides/pharmacology

KW - Tachycardia, Supraventricular/metabolism

KW - Tacrolimus/pharmacology

KW - Time Factors

KW - Transcription, Genetic

U2 - 10.1161/CIRCRESAHA.108.175463

DO - 10.1161/CIRCRESAHA.108.175463

M3 - Article

VL - 103

SP - 845

EP - 854

JO - Circulation Research

JF - Circulation Research

SN - 0009-7330

IS - 8

ER -