Ryanodine receptor-mediated calcium leak drives progressive development of an atrial fibrillation substrate in a transgenic mouse model

Na Li; David Y. Chiang; Sufen Wang; Qiongling Wang; Liang Sun; Niels Voigt; Jonathan L. Respress; Sameer Ather; Darlene G. Skapura; Valerie K. Jordan; Frank T. Horrigan; Wilhelm Schmitz; Frank U. Müller; Miguel Valderrábano; Stanley Nattel; Dobromir Dobrev; Xander H.T. Wehrens

doi:10.1161/CIRCULATIONAHA.113.006611

Ryanodine receptor-mediated calcium leak drives progressive development of an atrial fibrillation substrate in a transgenic mouse model

Na Li, David Y. Chiang, Sufen Wang, Qiongling Wang, Liang Sun, Niels Voigt, Jonathan L. Respress, Sameer Ather, Darlene G. Skapura, Valerie K. Jordan, Frank T. Horrigan, Wilhelm Schmitz, Frank U. Müller, Miguel Valderrábano, Stanley Nattel, Dobromir Dobrev, Xander H.T. Wehrens

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143 Scopus citations

Abstract

BACKGROUND - : The progression of atrial fibrillation (AF) from paroxysmal to persistent forms remains a major clinical challenge. Abnormal sarcoplasmic reticulum (SR) Ca leak via the ryanodine receptor type 2 (RyR2) has been observed as a source of ectopic activity in various AF models. However, its potential role in progression to long-lasting spontaneous AF (sAF) has never been tested. This study was designed to test the hypothesis that enhanced RyR2-mediated Ca release underlies the development of a substrate for sAF and to elucidate the underlying mechanisms. METHODS AND RESULTS - : CREM-IbΔC-X transgenic (CREM) mice developed age-dependent progression from spontaneous atrial ectopy to paroxysmal and eventually long-lasting AF. The development of sAF in CREM mice was preceded by enhanced diastolic Ca release, atrial enlargement, and marked conduction abnormalities. Genetic inhibition of Ca/calmodulin-dependent protein kinase II-mediated RyR2-S2814 phosphorylation in CREM mice normalized open probability of RyR2 channels and SR Ca release, delayed the development of spontaneous atrial ectopy, fully prevented sAF, suppressed atrial dilation, and forestalled atrial conduction abnormalities. Hyperactive RyR2 channels directly stimulated the Ca-dependent hypertrophic pathway nuclear factor of activated T cell/Rcan1-4, suggesting a role for the nuclear factor of activated T cell/Rcan1-4 system in the development of a substrate for long-lasting AF in CREM mice. CONCLUSIONS - : RyR2-mediated SR Ca leak directly underlies the development of a substrate for sAF in CREM mice, the first demonstration of a molecular mechanism underlying AF progression and sAF substrate development in an experimental model. Our work demonstrates that the role of abnormal diastolic Ca release in AF may not be restricted to the generation of atrial ectopy but extends to the development of atrial remodeling underlying the AF substrate.

Original language	English (US)
Pages (from-to)	1276-1285
Number of pages	10
Journal	Circulation
Volume	129
Issue number	12
DOIs	https://doi.org/10.1161/CIRCULATIONAHA.113.006611
State	Published - Mar 25 2014

Keywords

atrial fibrillation
calcium
mice
ryanodine receptor calcium release channel

ASJC Scopus subject areas

Physiology (medical)
Cardiology and Cardiovascular Medicine

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10.1161/CIRCULATIONAHA.113.006611

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Li, N., Chiang, D. Y., Wang, S., Wang, Q., Sun, L., Voigt, N., Respress, J. L., Ather, S., Skapura, D. G., Jordan, V. K., Horrigan, F. T., Schmitz, W., Müller, F. U., Valderrábano, M., Nattel, S., Dobrev, D., & Wehrens, X. H. T. (2014). Ryanodine receptor-mediated calcium leak drives progressive development of an atrial fibrillation substrate in a transgenic mouse model. Circulation, 129(12), 1276-1285. https://doi.org/10.1161/CIRCULATIONAHA.113.006611

Li, N, Chiang, DY, Wang, S, Wang, Q, Sun, L, Voigt, N, Respress, JL, Ather, S, Skapura, DG, Jordan, VK, Horrigan, FT, Schmitz, W, Müller, FU, Valderrábano, M, Nattel, S, Dobrev, D & Wehrens, XHT 2014, 'Ryanodine receptor-mediated calcium leak drives progressive development of an atrial fibrillation substrate in a transgenic mouse model', Circulation, vol. 129, no. 12, pp. 1276-1285. https://doi.org/10.1161/CIRCULATIONAHA.113.006611

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abstract = "BACKGROUND - : The progression of atrial fibrillation (AF) from paroxysmal to persistent forms remains a major clinical challenge. Abnormal sarcoplasmic reticulum (SR) Ca leak via the ryanodine receptor type 2 (RyR2) has been observed as a source of ectopic activity in various AF models. However, its potential role in progression to long-lasting spontaneous AF (sAF) has never been tested. This study was designed to test the hypothesis that enhanced RyR2-mediated Ca release underlies the development of a substrate for sAF and to elucidate the underlying mechanisms. METHODS AND RESULTS - : CREM-IbΔC-X transgenic (CREM) mice developed age-dependent progression from spontaneous atrial ectopy to paroxysmal and eventually long-lasting AF. The development of sAF in CREM mice was preceded by enhanced diastolic Ca release, atrial enlargement, and marked conduction abnormalities. Genetic inhibition of Ca/calmodulin-dependent protein kinase II-mediated RyR2-S2814 phosphorylation in CREM mice normalized open probability of RyR2 channels and SR Ca release, delayed the development of spontaneous atrial ectopy, fully prevented sAF, suppressed atrial dilation, and forestalled atrial conduction abnormalities. Hyperactive RyR2 channels directly stimulated the Ca-dependent hypertrophic pathway nuclear factor of activated T cell/Rcan1-4, suggesting a role for the nuclear factor of activated T cell/Rcan1-4 system in the development of a substrate for long-lasting AF in CREM mice. CONCLUSIONS - : RyR2-mediated SR Ca leak directly underlies the development of a substrate for sAF in CREM mice, the first demonstration of a molecular mechanism underlying AF progression and sAF substrate development in an experimental model. Our work demonstrates that the role of abnormal diastolic Ca release in AF may not be restricted to the generation of atrial ectopy but extends to the development of atrial remodeling underlying the AF substrate.",

keywords = "atrial fibrillation, calcium, mice, ryanodine receptor calcium release channel",

author = "Na Li and Chiang, {David Y.} and Sufen Wang and Qiongling Wang and Liang Sun and Niels Voigt and Respress, {Jonathan L.} and Sameer Ather and Skapura, {Darlene G.} and Jordan, {Valerie K.} and Horrigan, {Frank T.} and Wilhelm Schmitz and M{\"u}ller, {Frank U.} and Miguel Valderr{\'a}bano and Stanley Nattel and Dobromir Dobrev and Wehrens, {Xander H.T.}",

year = "2014",

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doi = "10.1161/CIRCULATIONAHA.113.006611",

language = "English (US)",

volume = "129",

pages = "1276--1285",

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T1 - Ryanodine receptor-mediated calcium leak drives progressive development of an atrial fibrillation substrate in a transgenic mouse model

AU - Li, Na

AU - Chiang, David Y.

AU - Wang, Sufen

AU - Wang, Qiongling

AU - Sun, Liang

AU - Voigt, Niels

AU - Respress, Jonathan L.

AU - Ather, Sameer

AU - Skapura, Darlene G.

AU - Jordan, Valerie K.

AU - Horrigan, Frank T.

AU - Schmitz, Wilhelm

AU - Müller, Frank U.

AU - Valderrábano, Miguel

AU - Nattel, Stanley

AU - Dobrev, Dobromir

AU - Wehrens, Xander H.T.

PY - 2014/3/25

Y1 - 2014/3/25

N2 - BACKGROUND - : The progression of atrial fibrillation (AF) from paroxysmal to persistent forms remains a major clinical challenge. Abnormal sarcoplasmic reticulum (SR) Ca leak via the ryanodine receptor type 2 (RyR2) has been observed as a source of ectopic activity in various AF models. However, its potential role in progression to long-lasting spontaneous AF (sAF) has never been tested. This study was designed to test the hypothesis that enhanced RyR2-mediated Ca release underlies the development of a substrate for sAF and to elucidate the underlying mechanisms. METHODS AND RESULTS - : CREM-IbΔC-X transgenic (CREM) mice developed age-dependent progression from spontaneous atrial ectopy to paroxysmal and eventually long-lasting AF. The development of sAF in CREM mice was preceded by enhanced diastolic Ca release, atrial enlargement, and marked conduction abnormalities. Genetic inhibition of Ca/calmodulin-dependent protein kinase II-mediated RyR2-S2814 phosphorylation in CREM mice normalized open probability of RyR2 channels and SR Ca release, delayed the development of spontaneous atrial ectopy, fully prevented sAF, suppressed atrial dilation, and forestalled atrial conduction abnormalities. Hyperactive RyR2 channels directly stimulated the Ca-dependent hypertrophic pathway nuclear factor of activated T cell/Rcan1-4, suggesting a role for the nuclear factor of activated T cell/Rcan1-4 system in the development of a substrate for long-lasting AF in CREM mice. CONCLUSIONS - : RyR2-mediated SR Ca leak directly underlies the development of a substrate for sAF in CREM mice, the first demonstration of a molecular mechanism underlying AF progression and sAF substrate development in an experimental model. Our work demonstrates that the role of abnormal diastolic Ca release in AF may not be restricted to the generation of atrial ectopy but extends to the development of atrial remodeling underlying the AF substrate.

AB - BACKGROUND - : The progression of atrial fibrillation (AF) from paroxysmal to persistent forms remains a major clinical challenge. Abnormal sarcoplasmic reticulum (SR) Ca leak via the ryanodine receptor type 2 (RyR2) has been observed as a source of ectopic activity in various AF models. However, its potential role in progression to long-lasting spontaneous AF (sAF) has never been tested. This study was designed to test the hypothesis that enhanced RyR2-mediated Ca release underlies the development of a substrate for sAF and to elucidate the underlying mechanisms. METHODS AND RESULTS - : CREM-IbΔC-X transgenic (CREM) mice developed age-dependent progression from spontaneous atrial ectopy to paroxysmal and eventually long-lasting AF. The development of sAF in CREM mice was preceded by enhanced diastolic Ca release, atrial enlargement, and marked conduction abnormalities. Genetic inhibition of Ca/calmodulin-dependent protein kinase II-mediated RyR2-S2814 phosphorylation in CREM mice normalized open probability of RyR2 channels and SR Ca release, delayed the development of spontaneous atrial ectopy, fully prevented sAF, suppressed atrial dilation, and forestalled atrial conduction abnormalities. Hyperactive RyR2 channels directly stimulated the Ca-dependent hypertrophic pathway nuclear factor of activated T cell/Rcan1-4, suggesting a role for the nuclear factor of activated T cell/Rcan1-4 system in the development of a substrate for long-lasting AF in CREM mice. CONCLUSIONS - : RyR2-mediated SR Ca leak directly underlies the development of a substrate for sAF in CREM mice, the first demonstration of a molecular mechanism underlying AF progression and sAF substrate development in an experimental model. Our work demonstrates that the role of abnormal diastolic Ca release in AF may not be restricted to the generation of atrial ectopy but extends to the development of atrial remodeling underlying the AF substrate.

KW - atrial fibrillation

KW - calcium

KW - mice

KW - ryanodine receptor calcium release channel

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Ryanodine receptor-mediated calcium leak drives progressive development of an atrial fibrillation substrate in a transgenic mouse model

Abstract

Keywords

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