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 inPflügers Archiv Vol. 475; no. 2; pp. 217 - 231
Main Authors Ko, Tae Hee, Jeong, Daun, Yu, Byeongil, Song, Ji Eun, Le, Qui Anh, Woo, Sun-Hee, Choi, Jong-Il
Format Journal Article
LanguageEnglish
Published Berlin/Heidelberg Springer Science and Business Media LLC 01.02.2023
Springer Berlin Heidelberg
Springer Nature B.V
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Online AccessGet full text
ISSN0031-6768
1432-2013
1432-2013
DOI10.1007/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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Issue 2
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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pubmed
crossref
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SourceType Open Access Repository
Aggregation Database
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Publisher
StartPage 217
SubjectTerms 1-Phosphatidylinositol 3-kinase
Action potential
Action Potentials
AKT protein
Atrial Fibrillation
Atrial Remodeling
Atrial Remodeling - physiology
Biomedical and Life Sciences
Biomedicine
Calcium imaging
Cardiac arrhythmia
Cell Biology
Cells
Electrical stimuli
Excitability
Heart Atria
Human Physiology
Humans
Immunofluorescence
Ion Channels
Ion Channels, Receptors and Transporters
Kinases
Molecular Medicine
Molecular modelling
Mutation
Myocytes
Myocytes, Cardiac
Myocytes, Cardiac - physiology
Neurosciences
Phosphatidylinositol 3-Kinase
Phosphatidylinositol 3-Kinase - pharmacology
Phosphatidylinositol 3-Kinases
Physiology
Proto-Oncogene Proteins c-akt
Receptors
Receptors and Transporters
Sodium
Sodium channels (voltage-gated)
Software
Therapeutic targets
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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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