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Epac activation, altered calcium homeostasis and ventricular arrhythmogenesis in the murine heart
The recently described exchange protein directly activated by cAMP (Epac) has been implicated in distinct protein kinase A-independent cellular signalling pathways. We investigated the role of Epac activation in adrenergically mediated ventricular arrhythmogenesis. In contrast to observations in con...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer-Verlag
2008
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3714550/ https://www.ncbi.nlm.nih.gov/pubmed/18600344 http://dx.doi.org/10.1007/s00424-008-0508-3 |
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author | Hothi, Sandeep S. Gurung, Iman S. Heathcote, Jennifer C. Zhang, Yanmin Booth, Stephen W. Skepper, Jeremy N. Grace, Andrew A. Huang, Christopher L.-H. |
author_facet | Hothi, Sandeep S. Gurung, Iman S. Heathcote, Jennifer C. Zhang, Yanmin Booth, Stephen W. Skepper, Jeremy N. Grace, Andrew A. Huang, Christopher L.-H. |
author_sort | Hothi, Sandeep S. |
collection | PubMed |
description | The recently described exchange protein directly activated by cAMP (Epac) has been implicated in distinct protein kinase A-independent cellular signalling pathways. We investigated the role of Epac activation in adrenergically mediated ventricular arrhythmogenesis. In contrast to observations in control conditions (n = 20), monophasic action potentials recorded in 2 of 10 intrinsically beating and 5 of 20 extrinsically paced Langendorff-perfused wild-type murine hearts perfused with the Epac activator 8-pCPT-2′-O-Me-cAMP (8-CPT, 1 μM) showed spontaneous triggered activity. Three of 20 such extrinsically paced hearts showed spontaneous ventricular tachycardia (VT). Programmed electrical stimulation provoked VT in 10 of 20 similarly treated hearts (P < 0.001; n = 20). However, there were no statistically significant accompanying changes (P > 0.05) in left ventricular epicardial (40.7 ± 1.2 versus 44.0 ± 1.7 ms; n = 10) or endocardial action potential durations (APD(90); 51.8 ± 2.3 versus 51.9 ± 2.2 ms; n = 10), transmural (ΔAPD(90)) (11.1 ± 2.6 versus 7.9 ± 2.8 ms; n = 10) or apico-basal repolarisation gradients, ventricular effective refractory periods (29.1 ± 1.7 versus 31.2 ± 2.4 ms in control and 8-CPT-treated hearts, respectively; n = 10) and APD(90) restitution characteristics. Nevertheless, fluorescence imaging of cytosolic Ca(2+) levels demonstrated abnormal Ca(2+) homeostasis in paced and resting isolated ventricular myocytes. Epac activation using isoproterenol in the presence of H-89 was also arrhythmogenic and similarly altered cellular Ca(2+) homeostasis. Epac-dependent effects were reduced by Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) inhibition with 1 μM KN-93. These findings associate VT in an intact cardiac preparation with altered cellular Ca(2+) homeostasis and Epac activation for the first time, in the absence of altered repolarisation gradients previously implicated in reentrant arrhythmias through a mechanism dependent on CaMKII activity. |
format | Online Article Text |
id | pubmed-3714550 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2008 |
publisher | Springer-Verlag |
record_format | MEDLINE/PubMed |
spelling | pubmed-37145502013-07-18 Epac activation, altered calcium homeostasis and ventricular arrhythmogenesis in the murine heart Hothi, Sandeep S. Gurung, Iman S. Heathcote, Jennifer C. Zhang, Yanmin Booth, Stephen W. Skepper, Jeremy N. Grace, Andrew A. Huang, Christopher L.-H. Pflugers Arch Cardiovascular Physiology The recently described exchange protein directly activated by cAMP (Epac) has been implicated in distinct protein kinase A-independent cellular signalling pathways. We investigated the role of Epac activation in adrenergically mediated ventricular arrhythmogenesis. In contrast to observations in control conditions (n = 20), monophasic action potentials recorded in 2 of 10 intrinsically beating and 5 of 20 extrinsically paced Langendorff-perfused wild-type murine hearts perfused with the Epac activator 8-pCPT-2′-O-Me-cAMP (8-CPT, 1 μM) showed spontaneous triggered activity. Three of 20 such extrinsically paced hearts showed spontaneous ventricular tachycardia (VT). Programmed electrical stimulation provoked VT in 10 of 20 similarly treated hearts (P < 0.001; n = 20). However, there were no statistically significant accompanying changes (P > 0.05) in left ventricular epicardial (40.7 ± 1.2 versus 44.0 ± 1.7 ms; n = 10) or endocardial action potential durations (APD(90); 51.8 ± 2.3 versus 51.9 ± 2.2 ms; n = 10), transmural (ΔAPD(90)) (11.1 ± 2.6 versus 7.9 ± 2.8 ms; n = 10) or apico-basal repolarisation gradients, ventricular effective refractory periods (29.1 ± 1.7 versus 31.2 ± 2.4 ms in control and 8-CPT-treated hearts, respectively; n = 10) and APD(90) restitution characteristics. Nevertheless, fluorescence imaging of cytosolic Ca(2+) levels demonstrated abnormal Ca(2+) homeostasis in paced and resting isolated ventricular myocytes. Epac activation using isoproterenol in the presence of H-89 was also arrhythmogenic and similarly altered cellular Ca(2+) homeostasis. Epac-dependent effects were reduced by Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) inhibition with 1 μM KN-93. These findings associate VT in an intact cardiac preparation with altered cellular Ca(2+) homeostasis and Epac activation for the first time, in the absence of altered repolarisation gradients previously implicated in reentrant arrhythmias through a mechanism dependent on CaMKII activity. Springer-Verlag 2008-07-04 2008 /pmc/articles/PMC3714550/ /pubmed/18600344 http://dx.doi.org/10.1007/s00424-008-0508-3 Text en © The Author(s) 2008 https://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited. |
spellingShingle | Cardiovascular Physiology Hothi, Sandeep S. Gurung, Iman S. Heathcote, Jennifer C. Zhang, Yanmin Booth, Stephen W. Skepper, Jeremy N. Grace, Andrew A. Huang, Christopher L.-H. Epac activation, altered calcium homeostasis and ventricular arrhythmogenesis in the murine heart |
title | Epac activation, altered calcium homeostasis and ventricular arrhythmogenesis in the murine heart |
title_full | Epac activation, altered calcium homeostasis and ventricular arrhythmogenesis in the murine heart |
title_fullStr | Epac activation, altered calcium homeostasis and ventricular arrhythmogenesis in the murine heart |
title_full_unstemmed | Epac activation, altered calcium homeostasis and ventricular arrhythmogenesis in the murine heart |
title_short | Epac activation, altered calcium homeostasis and ventricular arrhythmogenesis in the murine heart |
title_sort | epac activation, altered calcium homeostasis and ventricular arrhythmogenesis in the murine heart |
topic | Cardiovascular Physiology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3714550/ https://www.ncbi.nlm.nih.gov/pubmed/18600344 http://dx.doi.org/10.1007/s00424-008-0508-3 |
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