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Inducing Ito,f and phase 1 repolarization of the cardiac action potential with a Kv4.3/KChIP2.1 bicistronic transgene

Wang, Nan, Dries, Eef, Fowler, Ewan D., Harmer, Stephen C., Hancox, Jules C. and Cannell, Mark B. 2022. Inducing Ito,f and phase 1 repolarization of the cardiac action potential with a Kv4.3/KChIP2.1 bicistronic transgene. Journal of Molecular and Cellular Cardiology 164 , pp. 29-41. 10.1016/j.yjmcc.2021.11.004

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Abstract

The fast transient outward potassium current (Ito,f) plays a key role in phase 1 repolarization of the human cardiac action potential (AP) and its reduction in heart failure (HF) contributes to the loss of contractility. Therefore, restoring Ito,f might be beneficial for treating HF. The coding sequence of a P2A peptide was cloned, in frame, between Kv4.3 and KChIP2.1 genes and ribosomal skipping was confirmed by Western blotting. Typical Ito,f properties with slowed inactivation and accelerated recovery from inactivation due to the association of KChIP2.1 with Kv4.3 was seen in transfected HEK293 cells. Both bicistronic components trafficked to the plasmamembrane and in adenovirus transduced rabbit cardiomyocytes both t-tubular and sarcolemmal construct labelling appeared. The resulting current was similar to Ito,f seen in human ventricular cardiomyocytes and was 50% blocked at ~0.8 mmol/l 4-aminopyridine and increased ~30% by 5 μmol/l NS5806 (an Ito,f agonist). Variation in the density of the expressed Ito,f, in rabbit cardiomyocytes recapitulated typical species-dependent variations in AP morphology. Simultaneous voltage recording and intracellular Ca2+ imaging showed that modification of phase 1 to a non-failing human phenotype improved the rate of rise and magnitude of the Ca2+ transient. Ito,f expression also reduced AP triangulation but did not affect ICa,L and INa magnitudes. This raises the possibility for a new gene-based therapeutic approach to HF based on selective phase 1 modification.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Additional Information: This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
Publisher: Elsevier
ISSN: 0022-2828
Date of First Compliant Deposit: 30 March 2022
Date of Acceptance: 11 November 2021
Last Modified: 03 May 2023 22:31
URI: https://orca.cardiff.ac.uk/id/eprint/148916

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