mTOR Modulation of IKr through hERG1b-Dependent Mechanisms in Lipotoxic Heart

• Published in: International journal of molecular sciences 2022-07, Vol.23 (15), p.8061
• Main Authors: Aromolaran, Kelly A., Do, Jenny, Bernardi, Joyce, Aromolaran, Ademuyiwa S.
• Format: Article
• Language: English
• Subjects: Action potential; Atria; Cardiac arrhythmia; Channel gating; Electrophysiology; Feeding; Gene expression; Guinea pigs; High fat diet; Kinases; Kinetics; Low fat diet; Myocytes; Obesity; Palmitic acid; Pathogenesis; Proteins; Rapamycin; TOR protein
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms23158061

In the atria, the rapid delayed rectifier channel (IKr) is a critical contributor to repolarization. In lipotoxic atria, increased activity of the serine/threonine mammalian target of rapamycin (mTOR) may remodel IKr and predispose patients to arrhythmias. To investigate whether mTOR produced defects in IKr channel function (protein expression and gating mechanisms), electrophysiology and biochemical assays in HEK293 cells stably expressing hERG1a/1b, and adult guinea pig atrial myocytes were used. Feeding with the saturated fatty acid palmitic acid high-fat diet (HFD) was used to induce lipotoxicity. Lipotoxicity-challenged HEK293 cells displayed an increased density of hERG1a/1b currents due to a targeted and significant increase in hERG1b protein expression. Furthermore, lipotoxicity significantly slowed the hERG1a/1b inactivation kinetics, while the activation and deactivation remained essentially unchanged. mTOR complex 1 (mTORC1) inhibition with rapamycin (RAP) reversed the increase in hERG1a/1b density and inactivation. Compared to lipotoxic myocytes, RAP-treated cells displayed action potential durations (APDs) and IKr densities similar to those of controls. HFD feeding triggered arrhythmogenic changes (increased the IKr density and shortened the APD) in the atria, but this was not observed in low-fat-fed controls. The data are the first to show the modulation of IKr by mTORC1, possibly through the remodeling of hERG1b, in lipotoxic atrial myocytes. These results offer mechanistic insights with implications for targeted therapeutic options for the therapy of acquired supraventricular arrhythmias in obesity and associated pathologies.