Inhibition of late sodium current via PI3K/Akt signaling prevents cellular remodeling in tachypacing-induced HL-1 atrial myocytes

• Published in: Pflügers 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
• Language: English
• Published: Berlin/Heidelberg Springer Science and Business Media LLC 01.02.2023; Springer Berlin Heidelberg; Springer Nature B.V
• Subjects: 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; Tachypacing; PI3K/Akt signaling; Late sodium current; Electrical remodeling; Atrial Fibrillation
• ISSN: 0031-6768; 1432-2013; 1432-2013
• DOI: 10.1007/s00424-022-02754-z

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.