Cav1.3-C-terminus Restores Electrical and Contractile Functions in hiPSC-derived Cardiomyocytes Model of Heart Failure
Abstract
Objective: Heart failure (HF) is a major global health concern characterized by impaired excitation-contraction coupling and extensive structural remodeling of the myocardium, often modeled using a potent vasoactive and neurohumoral mediator, endothelin-1 (ET-1). This study investigates whether AAV6-mediated delivery of the Cav1.3-C-terminus, acting as an auto-trans-regulator of gene transcription, can restore electrophysiological and contractile functions in an ET-1-induced HF model using hiPSC-CMs.
Methods: hiPSC-CM monolayers were treated with 10 nM ET-1 for 48 hours to induce HF-like phenotype and then co-treated with an AAV6-Cav1.3-C-terminus. We subsequently evaluated gene expression via RT-qPCR, single-cell electrophysiological properties via patch-clamp, and contractile function using custom video analysis software.
Results: ET-1 treatment induced a HF-associated remodeling phenotype, characterized by significant upregulation of hypertrophic ( NPPA , NPPB , and ACTA1 ) and extracellular matrix-associated ( COL1A1 ) genes, along with increased cell membrane capacitance. This structural remodeling was accompanied by marked electrophysiological alterations, including downregulation of KCNH2 , CACNA1D , CACNA1C , and SCN5A , reduced potassium, calcium, and sodium current densities, and prolonged action potential duration. ET-1 impaired both the spontaneous beating rate and contraction amplitude of the monolayers. Co-treatment with the Cav1.3-C-terminus successfully restored CACNA1D and KCNH2 gene expression to baseline levels, accompanied by normalized L-type calcium and potassium current densities, normalized APD prolongation, and completely restored the chronotropic and inotropic functions to control levels.
Conclusions: ET-1-treated hiPSC-CMs model effectively recapitulates the electrophysiological and contractile dysregulations of HF. Gene therapy by Cav1.3-C-terminus provides robust functional rescue myocardial contractility, highlighting its potential as a novel therapeutic strategy for HF.
Significance statement: Heart failure (HF) involves structural, electrical and contractile dysfunctions with limited curative options. This study highlights a novel gene therapy utilizing the auto-trans-regulatory properties of the Cav1.3 C-terminus. In an endothelin-1-induced HF model using human induced pluripotent stem cells-derived cardiomyocytes (hiPSC-CMs), AAV6-mediated delivery of the Cav1.3-C-terminus successfully reversed pathological remodeling. By normalizing action potential duration, critical ion channel expression (CACNA1D, CACNA1C KCNH2), and rescuing mechanical contractility, this gene therapy approach offers a highly promising, targeted therapeutic strategy for tackling the complex pathophysiology of heart failure.
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BibTeX
@misc{sleiman2026cav13cterminus,
title = {{Cav1.3-C-terminus Restores Electrical and Contractile Functions in hiPSC-derived Cardiomyocytes Model of Heart Failure}},
author = {Yvonne Sleiman and Jean-Baptiste Reisqs and Mohamed Boutjdir},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.27.762268},
url = {https://www.biorxiv.org/content/10.64898/2026.10.27.762268v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Cav1.3-C-terminus Restores Electrical and Contractile Functions in hiPSC-derived Cardiomyocytes Model of Heart Failure
AU - Yvonne Sleiman
AU - Jean-Baptiste Reisqs
AU - Mohamed Boutjdir
PY - 2026
DA - 2026/10/27
PB - bioRxiv
DO - 10.64898/2026.10.27.762268
UR - https://www.biorxiv.org/content/10.64898/2026.10.27.762268v1
AB - Objective: Heart failure (HF) is a major global health concern characterized by impaired excitation-contraction coupling and extensive structural remodeling of the myocardium, often modeled using a potent vasoactive and neurohumoral mediator, endothelin-1 (ET-1). This study investigates whether AAV6-mediated delivery of the Cav1.3-C-terminus, acting as an auto-trans-regulator of gene transcription, can restore electrophysiological and contractile functions in an ET-1-induced HF model using hiPSC-CMs. Methods: hiPSC-CM monolayers were treated with 10 nM ET-1 for 48 hours to induce HF-like phenotype and then co-treated with an AAV6-Cav1.3-C-terminus. We subsequently evaluated gene expression via RT-qPCR, single-cell electrophysiological properties via patch-clamp, and contractile function using custom video analysis software. Results: ET-1 treatment induced a HF-associated remodeling phenotype, characterized by significant upregulation of hypertrophic ( NPPA , NPPB , and ACTA1 ) and extracellular matrix-associated ( COL1A1 ) genes, along with increased cell membrane capacitance. This structural remodeling was accompanied by marked electrophysiological alterations, including downregulation of KCNH2 , CACNA1D , CACNA1C , and SCN5A , reduced potassium, calcium, and sodium current densities, and prolonged action potential duration. ET-1 impaired both the spontaneous beating rate and contraction amplitude of the monolayers. Co-treatment with the Cav1.3-C-terminus successfully restored CACNA1D and KCNH2 gene expression to baseline levels, accompanied by normalized L-type calcium and potassium current densities, normalized APD prolongation, and completely restored the chronotropic and inotropic functions to control levels. Conclusions: ET-1-treated hiPSC-CMs model effectively recapitulates the electrophysiological and contractile dysregulations of HF. Gene therapy by Cav1.3-C-terminus provides robust functional rescue myocardial contractility, highlighting its potential as a novel therapeutic strategy for HF. Significance statement: Heart failure (HF) involves structural, electrical and contractile dysfunctions with limited curative options. This study highlights a novel gene therapy utilizing the auto-trans-regulatory properties of the Cav1.3 C-terminus. In an endothelin-1-induced HF model using human induced pluripotent stem cells-derived cardiomyocytes (hiPSC-CMs), AAV6-mediated delivery of the Cav1.3-C-terminus successfully reversed pathological remodeling. By normalizing action potential duration, critical ion channel expression (CACNA1D, CACNA1C KCNH2), and rescuing mechanical contractility, this gene therapy approach offers a highly promising, targeted therapeutic strategy for tackling the complex pathophysiology of heart failure.
SN - 2692-8205
ER -