RT Journal Article
T1 Two concurrent mechanisms are responsible for the INa increase produced by dapagliflozin and empagliflozin in healthy and heart failure cardiomyocytes
A1 Rapún, Josu
A1 Pérez Martín, Sara
A1 Cámara Checa, Anabel
A1 San José, Gorka
A1 Núñez Fernández, Roberto
A1 Crespo García, María Teresa
A1 Hoban, Adam
A1 Rubio Alarcón, Marcos
A1 Martínez Blanco, Elena
A1 Tamargo Menéndez, Juan
A1 Díez Guerra, F. Javier
A1 López, Begoña
A1 Gómez García, Ricardo
A1 González, Arantxa
A1 Delpón Mosquera, María Eva
A1 Caballero Collado, Ricardo
AB AbstractDapagliflozin and empagliflozin exert many cardiovascular protective actions in heart failure (HF) patients. HF-induced electrical remodelling decreases the expression of Nav1.5 channels (encoded by SCN5A) that generate the cardiac Na+ current (INa) impairing excitability and promoting arrhythmias. We aimed to mechanistically decipher the peak INa increase produced by dapagliflozin and empagliflozin in healthy and HF cardiomyocytes. We recorded macroscopic and single-channel currents and action potentials (AP) using the patch-clamp technique and generated a mouse model of HF with reduced ejection fraction by transverse aortic constriction (TAC). Single-channel recordings showed that dapagliflozin and empagliflozin (1 μM) increased the open probability (Po) of Nav1.5 channels by augmenting channel re-openings and the number of traces with openings and by doubling the open time constant, respectively. Both drugs increased SCN5A mRNA levels and the membrane expression of Nav1.5 channels. Empagliflozin also enhanced the cytoplasmic mobility of Nav1.5 channels. Molecular modelling and site-directed mutagenesis analysis demonstrated that both drugs bind to a previously unknown site at the Nav1.5 DIII-DIV fenestration. Dapagliflozin and empagliflozin hyperpolarized the resting membrane potential and increased the action potential amplitude in human cardiomyocytes derived from induced pluripotent stem cells. Importantly, in TAC cardiomyocytes dapagliflozin and empagliflozin restored the HF-reduced peak INa to control levels. Dapagliflozin and empagliflozin bind to a novel site within cardiac Nav1.5 increasing INa by augmenting the Po and the membrane expression of the channels. We hypothesized that this unique effects could be of interest for the treatment of arrhythmias associated with decreased Nav1.5 channel expression.
PB Elsevier
YR 2025
FD 2025-05
LK https://hdl.handle.net/20.500.14352/119732
UL https://hdl.handle.net/20.500.14352/119732
LA eng
NO Rapún J, Pérez-Martín S, Cámara-Checa A, San José G, Núñez-Fernández R, Crespo-García T, et al. Two concurrent mechanisms are responsible for the INa increase produced by dapagliflozin and empagliflozin in healthy and heart failure cardiomyocytes. Biomedicine & Pharmacotherapy 2025;186:117984. https://doi.org/10.1016/j.biopha.2025.117984.
DS Docta Complutense
RD 19 dic 2025