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Scn1b expression in the adult mouse heart modulates Na+ influx in myocytes and reveals a mechanistic link between Na+ entry and diastolic function

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Daniel O. Cervantes, Emanuele Pizzo, Harshada Ketkar, Sreema P. Parambath, Samantha Tang, Eleonora Cianflone, Antonio Cannata, Govindaiah Vinukonda, Sudhir Jain, Jason T. Jacobson, Marcello Rota

Original languageEnglish
Pages (from-to)H975-H993
JournalAmerican journal of physiology. Heart and circulatory physiology
Volume322
Issue number6
DOIs
Published1 Jun 2022

Bibliographical note

Funding Information: This work was supported by the National Institutes of Health Grants R01AG055407 and R01HL146628, American Heart Association Grant 19TPA34850067, and New York Medical College (NYMC) intramural resources, including NYMC Translational Science Institute funds. Publisher Copyright: Copyright © 2022 The Authors.

King's Authors

Abstract

Voltage-gated sodium channels (VGSCs) are macromolecular assemblies composed of a number of proteins regulating channel conductance and properties. VGSCs generate Na + current (I Na) in myocytes and play fundamental roles in excitability and impulse conduction in the heart. Moreover, VGSCs condition mechanical properties of the myocardium, a process that appears to involve the late component of I Na. Variants in the gene SCN1B, encoding the VGSC β1- and β1B-subunits, result in inherited neurological disorders and cardiac arrhythmias. But the precise contributions of β1/β1B-subunits and VGSC integrity to the overall function of the adult heart remain to be clarified. For this purpose, adult mice with cardiac-restricted, inducible deletion of Scn1b (conditional knockout, cKO) were studied. Myocytes from cKO mice had increased densities of fast (+ 20%)- and slow (+ 140%)-inactivating components of I Na, with respect to control cells. By echocardiography and invasive hemodynamics, systolic function was preserved in cKO mice, but diastolic properties and ventricular compliance were compromised, with respect to control animals. Importantly, inhibition of late I Na with GS967 normalized left ventricular filling pattern and isovolumic relaxation time in cKO mice. At the cellular level, cKO myocytes presented delayed kinetics of Ca 2+ transients and cell mechanics, defects that were corrected by inhibition of I Na. Collectively, these results document that VGSC β1/β1B-subunits modulate electrical and mechanical function of the heart by regulating, at least in part, Na + influx in cardiomyocytes.

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