British journal of pharmacology · 2026
Inhibition of late sodium current prevents pathological hyperactivation of calcium/calmodulin-dependent protein kinase IIδ in a murine model of acute doxorubicin-related cardiotoxicity.
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Feder Anna-Lena, Pfützenreuter Anna-Maria, Funke Lea Maria, Baier Maria Johanna, Tarnowski Daniel, Stengel Laura, Maier Lars Siegfried, Sag Can Martin
Аннотация
BACKGROUND AND PURPOSE: 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 INa and hyperactivation of CaMKIIδ. Increased [Na+]i contributes to CaMKIIδ activation through Na-dependent Ca2+ overload, and CaMKIIδ can further amplify late INa.
EXPERIMENTAL APPROACH: We tested whether pharmacological inhibition of the late INa 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 INa was tested in transgenic S571A cardiomyocytes lacking the CaMKII-specific phosphorylation site S571A on NaV1.5. Functional readouts were obtained using patch-clamp technique, as well as confocal and epifluorescence microscopy.
KEY RESULTS: DOX acutely increased late INa 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 INa by EMPA or RAN, and genetic deletion of the CaMKII-specific phosphorylation-site serine-571 at NaV1.5 prevented DOX-related stimulation of the late INa and subsequent CaMKIIδ hyperactivation, which functionally preserved intracellular Ca handling.
CONCLUSION AND IMPLICATIONS: Inhibition of late INa protects cardiomyocytes from pathologic CaMKIIδ hyperactivation and impaired Ca2+ handling in the setting of acute DOX cardiotoxicity.
EXPERIMENTAL APPROACH: We tested whether pharmacological inhibition of the late INa 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 INa was tested in transgenic S571A cardiomyocytes lacking the CaMKII-specific phosphorylation site S571A on NaV1.5. Functional readouts were obtained using patch-clamp technique, as well as confocal and epifluorescence microscopy.
KEY RESULTS: DOX acutely increased late INa 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 INa by EMPA or RAN, and genetic deletion of the CaMKII-specific phosphorylation-site serine-571 at NaV1.5 prevented DOX-related stimulation of the late INa and subsequent CaMKIIδ hyperactivation, which functionally preserved intracellular Ca handling.
CONCLUSION AND IMPLICATIONS: Inhibition of late INa protects cardiomyocytes from pathologic CaMKIIδ hyperactivation and impaired Ca2+ handling in the setting of acute DOX cardiotoxicity.