Nora Eccles Harrison Cardiovascular Research and Training Institute (CVRTI), University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
Masonic Medical Research Institute, Utica, NY 13501, USA.
Int J Mol Sci. 2022 Jul 22;23(15):8061. doi: 10.3390/ijms23158061.
In the atria, the rapid delayed rectifier channel () is a critical contributor to repolarization. In lipotoxic atria, increased activity of the serine/threonine mammalian target of rapamycin (mTOR) may remodel and predispose patients to arrhythmias. To investigate whether mTOR produced defects in 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 densities similar to those of controls. HFD feeding triggered arrhythmogenic changes (increased the 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 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.
在心房中，快速延迟整流钾通道（）是复极化的关键贡献者。在脂肪毒性的心房中，丝氨酸/苏氨酸哺乳动物雷帕霉素靶蛋白（mTOR）的活性增加可能会重塑，并使患者易发生心律失常。为了研究 mTOR 是否会导致通道功能（蛋白表达和门控机制）缺陷，我们使用稳定表达 hERG1a/1b 的 HEK293 细胞和成年豚鼠心房肌细胞进行了电生理学和生化分析。使用饱和脂肪酸棕榈酸高脂肪饮食（HFD）喂养来诱导脂肪毒性。脂肪毒性挑战的 HEK293 细胞由于 hERG1b 蛋白表达的靶向和显著增加而显示出 hERG1a/1b 电流密度增加。此外，脂肪毒性显著减慢了 hERG1a/1b 的失活动力学，而激活和去激活基本保持不变。用雷帕霉素（RAP）抑制 mTOR 复合物 1（mTORC1）逆转了 hERG1a/1b 密度和失活的增加。与脂肪毒性细胞相比，RAP 处理的细胞显示动作电位持续时间（APD）和密度与对照相似。HFD 喂养在心房中引发了致心律失常变化（增加了密度并缩短了 APD），但在低脂喂养对照组中未观察到这种变化。这些数据首次表明 mTORC1 可调节通道，可能通过 hERG1b 的重塑，在脂肪毒性心房肌细胞中。这些结果提供了机制上的见解，可能为肥胖症和相关病理中获得性室上性心律失常的靶向治疗选择提供了依据。
