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Reduced cardiomyocyte Na(+) current in the age‐dependent murine Pgc‐1β (−/−) model of ventricular arrhythmia
Peroxisome proliferator‐activated receptor‐γ coactivator‐1 deficient (Pgc‐1β (−/−)) murine hearts model the increased, age‐dependent, ventricular arrhythmic risks attributed to clinical conditions associated with mitochondrial energetic dysfunction. These were accompanied by compromised action poten...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6492124/ https://www.ncbi.nlm.nih.gov/pubmed/30146680 http://dx.doi.org/10.1002/jcp.27183 |
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author | Ahmad, Shiraz Valli, Haseeb Smyth, Robert Jiang, Anita Y. Jeevaratnam, Kamalan Matthews, Hugh R. Huang, Christopher L.‐H. |
author_facet | Ahmad, Shiraz Valli, Haseeb Smyth, Robert Jiang, Anita Y. Jeevaratnam, Kamalan Matthews, Hugh R. Huang, Christopher L.‐H. |
author_sort | Ahmad, Shiraz |
collection | PubMed |
description | Peroxisome proliferator‐activated receptor‐γ coactivator‐1 deficient (Pgc‐1β (−/−)) murine hearts model the increased, age‐dependent, ventricular arrhythmic risks attributed to clinical conditions associated with mitochondrial energetic dysfunction. These were accompanied by compromised action potential (AP) upstroke rates and impaired conduction velocities potentially producing arrhythmic substrate. We tested a hypothesis implicating compromised Na(+) current in these electrophysiological phenotypes by applying loose patch‐clamp techniques in intact young and aged, wild‐type (WT) and Pgc‐1β (−/−), ventricular cardiomyocyte preparations for the first time. This allowed conservation of their in vivo extracellular and intracellular conditions. Depolarising steps elicited typical voltage‐dependent activating and inactivating inward Na(+) currents with peak amplitudes increasing or decreasing with their respective activating or preceding inactivating voltage steps. Two‐way analysis of variance associated Pgc‐1β (−/−) genotype with independent reductions in maximum peak ventricular Na(+) currents from −36.63 ± 2.14 (n = 20) and −35.43 ± 1.96 (n = 18; young and aged WT, respectively), to −29.06 ± 1.65 (n = 23) and −27.93 ± 1.63 (n = 20; young and aged Pgc‐1β (−/−), respectively) pA/μm(2) (p < 0.0001), without independent effects of, or interactions with age. Voltages at half‐maximal current V*, and steepness factors k in plots of voltage dependences of both Na(+) current activation and inactivation, and time constants for its postrepolarisation recovery from inactivation, remained indistinguishable through all experimental groups. So were the activation and rectification properties of delayed outward (K(+)) currents, demonstrated from tail currents reflecting current recoveries from respective varying or constant voltage steps. These current–voltage properties directly implicate decreases specifically in maximum available Na(+) current with unchanged voltage dependences and unaltered K(+) current properties, in proarrhythmic reductions in AP conduction velocity in Pgc‐1β(−/−) ventricles. |
format | Online Article Text |
id | pubmed-6492124 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-64921242019-05-06 Reduced cardiomyocyte Na(+) current in the age‐dependent murine Pgc‐1β (−/−) model of ventricular arrhythmia Ahmad, Shiraz Valli, Haseeb Smyth, Robert Jiang, Anita Y. Jeevaratnam, Kamalan Matthews, Hugh R. Huang, Christopher L.‐H. J Cell Physiol Original Research Articles Peroxisome proliferator‐activated receptor‐γ coactivator‐1 deficient (Pgc‐1β (−/−)) murine hearts model the increased, age‐dependent, ventricular arrhythmic risks attributed to clinical conditions associated with mitochondrial energetic dysfunction. These were accompanied by compromised action potential (AP) upstroke rates and impaired conduction velocities potentially producing arrhythmic substrate. We tested a hypothesis implicating compromised Na(+) current in these electrophysiological phenotypes by applying loose patch‐clamp techniques in intact young and aged, wild‐type (WT) and Pgc‐1β (−/−), ventricular cardiomyocyte preparations for the first time. This allowed conservation of their in vivo extracellular and intracellular conditions. Depolarising steps elicited typical voltage‐dependent activating and inactivating inward Na(+) currents with peak amplitudes increasing or decreasing with their respective activating or preceding inactivating voltage steps. Two‐way analysis of variance associated Pgc‐1β (−/−) genotype with independent reductions in maximum peak ventricular Na(+) currents from −36.63 ± 2.14 (n = 20) and −35.43 ± 1.96 (n = 18; young and aged WT, respectively), to −29.06 ± 1.65 (n = 23) and −27.93 ± 1.63 (n = 20; young and aged Pgc‐1β (−/−), respectively) pA/μm(2) (p < 0.0001), without independent effects of, or interactions with age. Voltages at half‐maximal current V*, and steepness factors k in plots of voltage dependences of both Na(+) current activation and inactivation, and time constants for its postrepolarisation recovery from inactivation, remained indistinguishable through all experimental groups. So were the activation and rectification properties of delayed outward (K(+)) currents, demonstrated from tail currents reflecting current recoveries from respective varying or constant voltage steps. These current–voltage properties directly implicate decreases specifically in maximum available Na(+) current with unchanged voltage dependences and unaltered K(+) current properties, in proarrhythmic reductions in AP conduction velocity in Pgc‐1β(−/−) ventricles. John Wiley and Sons Inc. 2018-08-26 2019-04 /pmc/articles/PMC6492124/ /pubmed/30146680 http://dx.doi.org/10.1002/jcp.27183 Text en © 2018 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals, Inc. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Research Articles Ahmad, Shiraz Valli, Haseeb Smyth, Robert Jiang, Anita Y. Jeevaratnam, Kamalan Matthews, Hugh R. Huang, Christopher L.‐H. Reduced cardiomyocyte Na(+) current in the age‐dependent murine Pgc‐1β (−/−) model of ventricular arrhythmia |
title | Reduced cardiomyocyte Na(+) current in the age‐dependent murine Pgc‐1β
(−/−) model of ventricular arrhythmia |
title_full | Reduced cardiomyocyte Na(+) current in the age‐dependent murine Pgc‐1β
(−/−) model of ventricular arrhythmia |
title_fullStr | Reduced cardiomyocyte Na(+) current in the age‐dependent murine Pgc‐1β
(−/−) model of ventricular arrhythmia |
title_full_unstemmed | Reduced cardiomyocyte Na(+) current in the age‐dependent murine Pgc‐1β
(−/−) model of ventricular arrhythmia |
title_short | Reduced cardiomyocyte Na(+) current in the age‐dependent murine Pgc‐1β
(−/−) model of ventricular arrhythmia |
title_sort | reduced cardiomyocyte na(+) current in the age‐dependent murine pgc‐1β
(−/−) model of ventricular arrhythmia |
topic | Original Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6492124/ https://www.ncbi.nlm.nih.gov/pubmed/30146680 http://dx.doi.org/10.1002/jcp.27183 |
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