Inhibition of late sodium current prevents pathological hyperactivation of calcium/calmodulin-dependent protein kinase IIδ in a murine model of acute doxorubicin-related cardiotoxicity.

Authors

Anna-Lena Feder, Anna-Maria Pfützenreuter, Lea Maria Funke, Maria Johanna Baier, Daniel Tarnowski, Laura Stengel, Lars Siegfried Maier, Can Martin Sag

Published in

British journal of pharmacology. Jul 28, 2026. Epub Jul 28, 2026.

Abstract

Doxorubicin (DOX) is a highly effective anthracycline, whose clinical application for cancer is limited by cardiotoxicity. The mechanisms underlying doxorubicin-induced toxic cardiomyopathy (DICM) involve electrophysiological remodelling with intracellular Na⁺ overload because of increased late I_Na and hyperactivation of CaMKIIδ. Increased [Na⁺]_i contributes to CaMKIIδ activation through Na-dependent Ca²⁺ overload, and CaMKIIδ can further amplify late I_Na.
We tested whether pharmacological inhibition of the late I_Na by either ranolazine (RAN, 10 μmol·L^-1) or empagliflozin (EMPA, 1 μmol·L^-1) is sufficient to attenuate DOX-mediated hyperactivation of CaMKIIδ in isolated wildtype (WT) ventricular cardiomyocytes. The contribution of reciprocal CaMKII-dependent stimulation of late I_Na was tested in transgenic S571A cardiomyocytes lacking the CaMKII-specific phosphorylation site S571A on Na_V1.5. Functional readouts were obtained using patch-clamp technique, as well as confocal and epifluorescence microscopy.
DOX acutely increased late I_Na in WT cardiomyocytes by twofold, which was associated with redox- and phospho-dependent activation of CaMKIIδ. Hyperactivated CaMKIIδ led to acutely impaired Ca²⁺ handling because of diastolic Ca²⁺ loss from the sarcoplasmic reticulum (SR) mediated by phosphorylation of the RyR2 at the CaMKII-specific phosphorylation site serine-2814. Pharmacological inhibition of late I_Na by EMPA or RAN, and genetic deletion of the CaMKII-specific phosphorylation-site serine-571 at Na_V1.5 prevented DOX-related stimulation of the late I_Na and subsequent CaMKIIδ hyperactivation, which functionally preserved intracellular Ca handling.
Inhibition of late I_Na protects cardiomyocytes from pathologic CaMKIIδ hyperactivation and impaired Ca²⁺ handling in the setting of acute DOX cardiotoxicity.

PMID:
42522188
Bibliographic data and abstract were imported from PubMed on 29 Jul 2026.

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