Inhibition of late sodium current via PI3K/Akt signaling prevents cellular remodeling in tachypacing-induced HL-1 atrial myocytes
An aberrant late sodium current ( I Na,Late ) caused by a mutation in the cardiac sodium channel (Na v 1.5) has emerged as a contributor to electrical remodeling that causes susceptibility to atrial fibrillation (AF). Although downregulation of phosphoinositide 3-kinase (PI3K)/Akt signaling is assoc...
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Published in | Pflügers Archiv Vol. 475; no. 2; pp. 217 - 231 |
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Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
Published |
Berlin/Heidelberg
Springer Science and Business Media LLC
01.02.2023
Springer Berlin Heidelberg Springer Nature B.V |
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Online Access | Get full text |
ISSN | 0031-6768 1432-2013 1432-2013 |
DOI | 10.1007/s00424-022-02754-z |
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Abstract | An aberrant late sodium current (
I
Na,Late
) caused by a mutation in the cardiac sodium channel (Na
v
1.5) has emerged as a contributor to electrical remodeling that causes susceptibility to atrial fibrillation (AF). Although downregulation of phosphoinositide 3-kinase (PI3K)/Akt signaling is associated with AF, the molecular mechanisms underlying the negative regulation of
I
Na,Late
in AF remain unclear, and potential therapeutic approaches are needed. In this work, we constructed a tachypacing-induced cellular model of AF by exposing HL-1 myocytes to rapid electrical stimulation (1.5 V/cm, 4 ms, 10 Hz) for 6 h. Then, we gathered data using confocal Ca
2+
imaging, immunofluorescence, patch-clamp recordings, and immunoblots. The tachypacing cells displayed irregular Ca
2+
release, delayed afterdepolarization, prolonged action potential duration, and reduced PI3K/Akt signaling compared with controls. Those detrimental effects were related to increased
I
Na,Late
and were significantly mediated by treatment with the
I
Na,Late
blocker ranolazine. Furthermore, decreased PI3K/Akt signaling via PI3K inhibition increased
I
Na,Late
and subsequent aberrant myocyte excitability, which were abolished by
I
Na,Late
inhibition, suggesting that PI3K/Akt signaling is responsible for regulating pathogenic
I
Na,Late
. These results indicate that PI3K/Akt signaling is critical for regulating
I
Na,Late
and electrical remodeling, supporting the use of PI3K/Akt-mediated
I
Na,Late
as a therapeutic target for AF. |
---|---|
AbstractList | An aberrant late sodium current (
I
Na,Late
) caused by a mutation in the cardiac sodium channel (Na
v
1.5) has emerged as a contributor to electrical remodeling that causes susceptibility to atrial fibrillation (AF). Although downregulation of phosphoinositide 3-kinase (PI3K)/Akt signaling is associated with AF, the molecular mechanisms underlying the negative regulation of
I
Na,Late
in AF remain unclear, and potential therapeutic approaches are needed. In this work, we constructed a tachypacing-induced cellular model of AF by exposing HL-1 myocytes to rapid electrical stimulation (1.5 V/cm, 4 ms, 10 Hz) for 6 h. Then, we gathered data using confocal Ca
2+
imaging, immunofluorescence, patch-clamp recordings, and immunoblots. The tachypacing cells displayed irregular Ca
2+
release, delayed afterdepolarization, prolonged action potential duration, and reduced PI3K/Akt signaling compared with controls. Those detrimental effects were related to increased
I
Na,Late
and were significantly mediated by treatment with the
I
Na,Late
blocker ranolazine. Furthermore, decreased PI3K/Akt signaling via PI3K inhibition increased
I
Na,Late
and subsequent aberrant myocyte excitability, which were abolished by
I
Na,Late
inhibition, suggesting that PI3K/Akt signaling is responsible for regulating pathogenic
I
Na,Late
. These results indicate that PI3K/Akt signaling is critical for regulating
I
Na,Late
and electrical remodeling, supporting the use of PI3K/Akt-mediated
I
Na,Late
as a therapeutic target for AF. An aberrant late sodium current (INa,Late) caused by a mutation in the cardiac sodium channel (Nav1.5) has emerged as a contributor to electrical remodeling that causes susceptibility to atrial fibrillation (AF). Although downregulation of phosphoinositide 3-kinase (PI3K)/Akt signaling is associated with AF, the molecular mechanisms underlying the negative regulation of INa,Late in AF remain unclear, and potential therapeutic approaches are needed. In this work, we constructed a tachypacing-induced cellular model of AF by exposing HL-1 myocytes to rapid electrical stimulation (1.5 V/cm, 4 ms, 10 Hz) for 6 h. Then, we gathered data using confocal Ca2+ imaging, immunofluorescence, patch-clamp recordings, and immunoblots. The tachypacing cells displayed irregular Ca2+ release, delayed afterdepolarization, prolonged action potential duration, and reduced PI3K/Akt signaling compared with controls. Those detrimental effects were related to increased INa,Late and were significantly mediated by treatment with the INa,Late blocker ranolazine. Furthermore, decreased PI3K/Akt signaling via PI3K inhibition increased INa,Late and subsequent aberrant myocyte excitability, which were abolished by INa,Late inhibition, suggesting that PI3K/Akt signaling is responsible for regulating pathogenic INa,Late. These results indicate that PI3K/Akt signaling is critical for regulating INa,Late and electrical remodeling, supporting the use of PI3K/Akt-mediated INa,Late as a therapeutic target for AF.An aberrant late sodium current (INa,Late) caused by a mutation in the cardiac sodium channel (Nav1.5) has emerged as a contributor to electrical remodeling that causes susceptibility to atrial fibrillation (AF). Although downregulation of phosphoinositide 3-kinase (PI3K)/Akt signaling is associated with AF, the molecular mechanisms underlying the negative regulation of INa,Late in AF remain unclear, and potential therapeutic approaches are needed. In this work, we constructed a tachypacing-induced cellular model of AF by exposing HL-1 myocytes to rapid electrical stimulation (1.5 V/cm, 4 ms, 10 Hz) for 6 h. Then, we gathered data using confocal Ca2+ imaging, immunofluorescence, patch-clamp recordings, and immunoblots. The tachypacing cells displayed irregular Ca2+ release, delayed afterdepolarization, prolonged action potential duration, and reduced PI3K/Akt signaling compared with controls. Those detrimental effects were related to increased INa,Late and were significantly mediated by treatment with the INa,Late blocker ranolazine. Furthermore, decreased PI3K/Akt signaling via PI3K inhibition increased INa,Late and subsequent aberrant myocyte excitability, which were abolished by INa,Late inhibition, suggesting that PI3K/Akt signaling is responsible for regulating pathogenic INa,Late. These results indicate that PI3K/Akt signaling is critical for regulating INa,Late and electrical remodeling, supporting the use of PI3K/Akt-mediated INa,Late as a therapeutic target for AF. AbstractAn aberrant late sodium current (INa,Late) caused by a mutation in the cardiac sodium channel (Nav1.5) has emerged as a contributor to electrical remodeling that causes susceptibility to atrial fibrillation (AF). Although downregulation of phosphoinositide 3-kinase (PI3K)/Akt signaling is associated with AF, the molecular mechanisms underlying the negative regulation of INa,Late in AF remain unclear, and potential therapeutic approaches are needed. In this work, we constructed a tachypacing-induced cellular model of AF by exposing HL-1 myocytes to rapid electrical stimulation (1.5 V/cm, 4 ms, 10 Hz) for 6 h. Then, we gathered data using confocal Ca2+ imaging, immunofluorescence, patch-clamp recordings, and immunoblots. The tachypacing cells displayed irregular Ca2+ release, delayed afterdepolarization, prolonged action potential duration, and reduced PI3K/Akt signaling compared with controls. Those detrimental effects were related to increased INa,Late and were significantly mediated by treatment with the INa,Late blocker ranolazine. Furthermore, decreased PI3K/Akt signaling via PI3K inhibition increased INa,Late and subsequent aberrant myocyte excitability, which were abolished by INa,Late inhibition, suggesting that PI3K/Akt signaling is responsible for regulating pathogenic INa,Late. These results indicate that PI3K/Akt signaling is critical for regulating INa,Late and electrical remodeling, supporting the use of PI3K/Akt-mediated INa,Late as a therapeutic target for AF. An aberrant late sodium current (I ) caused by a mutation in the cardiac sodium channel (Na 1.5) has emerged as a contributor to electrical remodeling that causes susceptibility to atrial fibrillation (AF). Although downregulation of phosphoinositide 3-kinase (PI3K)/Akt signaling is associated with AF, the molecular mechanisms underlying the negative regulation of I in AF remain unclear, and potential therapeutic approaches are needed. In this work, we constructed a tachypacing-induced cellular model of AF by exposing HL-1 myocytes to rapid electrical stimulation (1.5 V/cm, 4 ms, 10 Hz) for 6 h. Then, we gathered data using confocal Ca imaging, immunofluorescence, patch-clamp recordings, and immunoblots. The tachypacing cells displayed irregular Ca release, delayed afterdepolarization, prolonged action potential duration, and reduced PI3K/Akt signaling compared with controls. Those detrimental effects were related to increased I and were significantly mediated by treatment with the I blocker ranolazine. Furthermore, decreased PI3K/Akt signaling via PI3K inhibition increased I and subsequent aberrant myocyte excitability, which were abolished by I inhibition, suggesting that PI3K/Akt signaling is responsible for regulating pathogenic I . These results indicate that PI3K/Akt signaling is critical for regulating I and electrical remodeling, supporting the use of PI3K/Akt-mediated I as a therapeutic target for AF. |
Author | Sun-Hee Woo Qui Anh Le Daun Jeong Byeongil Yu Jong-Il Choi Ji Eun Song Tae Hee Ko |
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Keywords | Tachypacing PI3K/Akt signaling Late sodium current Electrical remodeling Atrial Fibrillation |
Language | English |
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Snippet | An aberrant late sodium current (
I
Na,Late
) caused by a mutation in the cardiac sodium channel (Na
v
1.5) has emerged as a contributor to electrical... An aberrant late sodium current (I ) caused by a mutation in the cardiac sodium channel (Na 1.5) has emerged as a contributor to electrical remodeling that... AbstractAn aberrant late sodium current (INa,Late) caused by a mutation in the cardiac sodium channel (Nav1.5) has emerged as a contributor to electrical... An aberrant late sodium current (INa,Late) caused by a mutation in the cardiac sodium channel (Nav1.5) has emerged as a contributor to electrical remodeling... |
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Title | Inhibition of late sodium current via PI3K/Akt signaling prevents cellular remodeling in tachypacing-induced HL-1 atrial myocytes |
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