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

Abstract

An aberrant late sodium current (I-Na,I-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,I-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 I-Na,I-Late and were significantly mediated by treatment with the I-Na,I-Late blocker ranolazine. Furthermore, decreased PI3K/Akt signaling via PI3K inhibition increased I-Na,I-Late and subsequent aberrant myocyte excitability, which were abolished by I-Na,I-Late inhibition, suggesting that PI3K/Akt signaling is responsible for regulating pathogenic I-Na,I-Late. These results indicate that PI3K/Akt signaling is critical for regulating I-Na,I-Late and electrical remodeling, supporting the use of PI3K/Akt-mediated I-Na,I-Late as a therapeutic target for AF.