Sauer Jakob, Marksteiner Jessica, Hohenegger Martin, Todt Hannes, Kubista Helmut, Dostal Christopher, Kiss Attila, Podesser Bruno K, Salzer Isabella, Koenig Xaver, Stary-Weinzinger Anna, Hilber Karlheinz, Kudlacek Oliver
Department of Neurophysiology and Neuropharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.
Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.
Am J Physiol Heart Circ Physiol. 2025 Sep 1;329(3):H680-H695. doi: 10.1152/ajpheart.00363.2025. Epub 2025 Aug 12.
Diminished peak sodium current () is a causative factor for slowed ventricular conduction and cardiac arrhythmias in patients with Duchenne muscular dystrophy (DMD), a devastating muscle disease triggered by dystrophin deficiency. Recently, we showed that chronic administration of the sodium/glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (EMPA) restores diminished peak in ventricular cardiomyocytes from the dystrophin-deficient mouse model of DMD. Here, we aimed to elucidate the underlying mechanism. Whole cell patch clamp studies revealed that 24-h incubation of dystrophic () ventricular cardiomyocytes with EMPA significantly increases peak in a concentration-dependent manner (EC = 94 nM). The enhancing effect on peak also occurred in dystrophic cardiac Purkinje fibers, as well as in dystrophic (DMD) rat cardiomyocytes, and was also exerted by other SGLT2 inhibitors. Immunofluorescence studies suggested that chronic EMPA treatment fully restores wild-type Na1.5 plasma membrane expression in cardiomyocytes. Peak enhancement by EMPA depended on functional anterograde trafficking of Na1.5. The local anesthetic mexiletine, a well-known pharmacological chaperone of Na1.5, enhanced peak in a similar manner to EMPA. Furthermore, mutation of human Na1.5 at a site important for local anesthetic binding (Y1767A) completely abolished the ability of both EMPA and mexiletine to enhance peak . Finally, the importance of Y1767 for drug-induced modulation of peak was confirmed by molecular docking simulations. Our findings suggest that EMPA acts as a pharmacological chaperone of Na1.5 channels. Its chronic administration may reduce arrhythmia vulnerability in patients with DMD and other arrhythmogenic pathologies associated with diminished peak . Dystrophin deficiency in cardiomyocytes leads to diminished peak Na currents. These can be fully rescued by long-term treatment with empagliflozin via pharmacochaperoning of Na1.5 channels.
钠电流峰值降低是杜氏肌营养不良症（DMD）患者心室传导减慢和心律失常的一个致病因素，DMD是一种由肌营养不良蛋白缺乏引发的严重肌肉疾病。最近，我们发现长期给予钠/葡萄糖协同转运蛋白2（SGLT2）抑制剂恩格列净（EMPA）可恢复DMD肌营养不良蛋白缺陷小鼠模型心室心肌细胞中降低的钠电流峰值。在此，我们旨在阐明其潜在机制。全细胞膜片钳研究表明，用EMPA孵育营养不良的心室心肌细胞24小时，可显著以浓度依赖的方式增加钠电流峰值（半数有效浓度=94 nM）。对钠电流峰值的增强作用也出现在营养不良的心脏浦肯野纤维以及营养不良的（DMD）大鼠心肌细胞中，其他SGLT2抑制剂也有此作用。免疫荧光研究表明，长期EMPA治疗可完全恢复心肌细胞中野生型Na1.5质膜表达。EMPA对钠电流峰值的增强作用依赖于Na1.5的功能性顺向转运。局部麻醉药美西律是一种著名的Na1.5药理学伴侣，其增强钠电流峰值的方式与EMPA相似。此外，人类Na1.5在对局部麻醉药结合重要的位点（Y1767A）发生突变，完全消除了EMPA和美西律增强钠电流峰值的能力。最后，通过分子对接模拟证实了Y1767对药物诱导的钠电流峰值调节的重要性。我们的研究结果表明，EMPA可作为Na1.5通道的药理学伴侣。长期给予EMPA可能会降低DMD患者以及其他与钠电流峰值降低相关的致心律失常疾病患者的心律失常易感性。心肌细胞中的肌营养不良蛋白缺乏会导致钠电流峰值降低。通过对Na1.5通道进行药物伴侣作用，长期使用恩格列净可完全挽救这些情况。
