RRAD-reduction reveals efficacy of targeting L-type calcium channel regulation for treatment of heart failure

Garrett Elmore; Sarisha S. Lohano; Nicholas M. McVay; Bryana M. Levitan; Andrea Sebastian; Kyle W. Barker; Alec Dupont; Steven W. Leung; Riham R.E. Abouleisa; Pretty R. Mathew; Austin Wellette-Hunsucker; Austin T. Minton; Kenneth S. Campbell; Solomon W. Harrar; Mohammad Mehri; Jonathan F. Wenk; Tamer M.A. Mohamed; Douglas A. Andres; Jonathan Satin

doi:10.1093/cvr/cvaf169

RRAD-reduction reveals efficacy of targeting L-type calcium channel regulation for treatment of heart failure

Garrett Elmore, Sarisha S. Lohano, Nicholas M. McVay, Bryana M. Levitan, Andrea Sebastian, Kyle W. Barker, Alec Dupont, Steven W. Leung, Riham R.E. Abouleisa, Pretty R. Mathew, Austin Wellette-Hunsucker, Austin T. Minton, Kenneth S. Campbell, Solomon W. Harrar, Mohammad Mehri, Jonathan F. Wenk, Tamer M.A. Mohamed, Douglas A. Andres, Jonathan Satin

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

Abstract

Aims Heart failure with reduced ejection fraction (HFrEF) is a major health problem. Increasing L-type calcium channel (LTCC) activity deteriorates heart function; however, myocardial RRAD knockout (cRADΔ/Δ) instills tonic modulated LTCC current (ICa,L) that preserves healthy myocardium. Thus, we chose to challenge the dogma that enhanced trigger Ca2+ is maladaptive. The study objective was to test the hypothesis that modulated ICa,L in cRADΔ/Δ mice rescues dilated cardiomyopathy by providing tonic modulated trigger Ca2+. Methods and results Mouse and human models were tested. The muscle lim protein knockout mouse (MLPKO) is a murine model of dilated cardiomyopathy (DCM) and HFrEF. The experimental timeline was to induce cRADΔ/Δ after onset of DCM (2.5 months of age) and follow subjects for up to 1-year. Longitudinal echocardiography and cardiac magnetic resonance imaging (CMR) showed that cRADΔ/Δ intervention rescued systolic function. Patch clamp recordings of isolated cardiomyocytes of MLPKO with cRADΔ/Δ demonstrated augmented LTCC activity, along with rescue of dysfunctional Ca2+ handling and sarcomere function. Bulk RNAseq of hearts demonstrated down-regulated pathological signalling cascades and pro-hypertrophic gene expression which comported with the reduction in eccentric hypertrophy observed with gravimetrics, CMR, and echocardiography. RRAD knockdown effects translate from mouse to human heart. Ventricle slices from HFrEF patients were treated with lentiviral shRNA targeting RRAD and recapitulated the inotropic and lusitropic effects observed in the mouse model of DCM. Conclusion Induction of cardiomyocyte-restricted RAD knockout in MLPKO mice after onset of DCM rescued cardiac dysfunction and attenuated pathological remodelling. cRADΔ/Δ intervention provided positive inotropy and lusitropy and reverted transcriptional signatures towards healthy myocardium. This study introduces targeting myocardial RAD regulation of the LTCC as a novel therapeutic strategy for systolic heart failure.

Original language	English
Pages (from-to)	2204-2221
Number of pages	18
Journal	Cardiovascular Research
Volume	121
Issue number	14
DOIs	https://doi.org/10.1093/cvr/cvaf169
State	Published - Oct 1 2025

Bibliographical note

Publisher Copyright:
© 2025 The Author(s). Published by Oxford University Press on behalf of the European Society of Cardiology.

Funding

This work is supported by US Department of Defense grants W81WXH-20-21-0418, HT94252310655; National Institutes of Health HL166280 and HL149164.

Funders	Funder number
U.S. Department of Defense	HT94252310655, W81WXH-20-21-0418
National Institutes of Health (NIH)	HL166280, HL149164

Keywords

Dilated cardiomyopathy
Heart failure
L-type calcium channel
Therapeutic strategy

ASJC Scopus subject areas

Physiology
Cardiology and Cardiovascular Medicine
Physiology (medical)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1093/cvr/cvaf169

Cite this

Elmore, G., Lohano, S. S., McVay, N. M., Levitan, B. M., Sebastian, A., Barker, K. W., Dupont, A., Leung, S. W., Abouleisa, R. R. E., Mathew, P. R., Wellette-Hunsucker, A., Minton, A. T., Campbell, K. S., Harrar, S. W., Mehri, M., Wenk, J. F., Mohamed, T. M. A., Andres, D. A., & Satin, J. (2025). RRAD-reduction reveals efficacy of targeting L-type calcium channel regulation for treatment of heart failure. Cardiovascular Research, 121(14), 2204-2221. https://doi.org/10.1093/cvr/cvaf169

@article{1b0350d55bee425db0fdc95ff908aa72,

title = "RRAD-reduction reveals efficacy of targeting L-type calcium channel regulation for treatment of heart failure",

abstract = "Aims Heart failure with reduced ejection fraction (HFrEF) is a major health problem. Increasing L-type calcium channel (LTCC) activity deteriorates heart function; however, myocardial RRAD knockout (cRADΔ/Δ) instills tonic modulated LTCC current (ICa,L) that preserves healthy myocardium. Thus, we chose to challenge the dogma that enhanced trigger Ca2+ is maladaptive. The study objective was to test the hypothesis that modulated ICa,L in cRADΔ/Δ mice rescues dilated cardiomyopathy by providing tonic modulated trigger Ca2+. Methods and results Mouse and human models were tested. The muscle lim protein knockout mouse (MLPKO) is a murine model of dilated cardiomyopathy (DCM) and HFrEF. The experimental timeline was to induce cRADΔ/Δ after onset of DCM (2.5 months of age) and follow subjects for up to 1-year. Longitudinal echocardiography and cardiac magnetic resonance imaging (CMR) showed that cRADΔ/Δ intervention rescued systolic function. Patch clamp recordings of isolated cardiomyocytes of MLPKO with cRADΔ/Δ demonstrated augmented LTCC activity, along with rescue of dysfunctional Ca2+ handling and sarcomere function. Bulk RNAseq of hearts demonstrated down-regulated pathological signalling cascades and pro-hypertrophic gene expression which comported with the reduction in eccentric hypertrophy observed with gravimetrics, CMR, and echocardiography. RRAD knockdown effects translate from mouse to human heart. Ventricle slices from HFrEF patients were treated with lentiviral shRNA targeting RRAD and recapitulated the inotropic and lusitropic effects observed in the mouse model of DCM. Conclusion Induction of cardiomyocyte-restricted RAD knockout in MLPKO mice after onset of DCM rescued cardiac dysfunction and attenuated pathological remodelling. cRADΔ/Δ intervention provided positive inotropy and lusitropy and reverted transcriptional signatures towards healthy myocardium. This study introduces targeting myocardial RAD regulation of the LTCC as a novel therapeutic strategy for systolic heart failure.",

keywords = "Dilated cardiomyopathy, Heart failure, L-type calcium channel, Therapeutic strategy",

author = "Garrett Elmore and Lohano, \{Sarisha S.\} and McVay, \{Nicholas M.\} and Levitan, \{Bryana M.\} and Andrea Sebastian and Barker, \{Kyle W.\} and Alec Dupont and Leung, \{Steven W.\} and Abouleisa, \{Riham R.E.\} and Mathew, \{Pretty R.\} and Austin Wellette-Hunsucker and Minton, \{Austin T.\} and Campbell, \{Kenneth S.\} and Harrar, \{Solomon W.\} and Mohammad Mehri and Wenk, \{Jonathan F.\} and Mohamed, \{Tamer M.A.\} and Andres, \{Douglas A.\} and Jonathan Satin",

note = "Publisher Copyright: {\textcopyright} 2025 The Author(s). Published by Oxford University Press on behalf of the European Society of Cardiology.",

year = "2025",

month = oct,

day = "1",

doi = "10.1093/cvr/cvaf169",

language = "English",

volume = "121",

pages = "2204--2221",

number = "14",

}

Elmore, G, Lohano, SS, McVay, NM, Levitan, BM, Sebastian, A, Barker, KW, Dupont, A, Leung, SW, Abouleisa, RRE, Mathew, PR, Wellette-Hunsucker, A, Minton, AT, Campbell, KS , Harrar, SW, Mehri, M, Wenk, JF, Mohamed, TMA, Andres, DA & Satin, J 2025, 'RRAD-reduction reveals efficacy of targeting L-type calcium channel regulation for treatment of heart failure', Cardiovascular Research, vol. 121, no. 14, pp. 2204-2221. https://doi.org/10.1093/cvr/cvaf169

TY - JOUR

T1 - RRAD-reduction reveals efficacy of targeting L-type calcium channel regulation for treatment of heart failure

AU - Elmore, Garrett

AU - Lohano, Sarisha S.

AU - McVay, Nicholas M.

AU - Levitan, Bryana M.

AU - Sebastian, Andrea

AU - Barker, Kyle W.

AU - Dupont, Alec

AU - Leung, Steven W.

AU - Abouleisa, Riham R.E.

AU - Mathew, Pretty R.

AU - Wellette-Hunsucker, Austin

AU - Minton, Austin T.

AU - Campbell, Kenneth S.

AU - Harrar, Solomon W.

AU - Mehri, Mohammad

AU - Wenk, Jonathan F.

AU - Mohamed, Tamer M.A.

AU - Andres, Douglas A.

AU - Satin, Jonathan

PY - 2025/10/1

Y1 - 2025/10/1

N2 - Aims Heart failure with reduced ejection fraction (HFrEF) is a major health problem. Increasing L-type calcium channel (LTCC) activity deteriorates heart function; however, myocardial RRAD knockout (cRADΔ/Δ) instills tonic modulated LTCC current (ICa,L) that preserves healthy myocardium. Thus, we chose to challenge the dogma that enhanced trigger Ca2+ is maladaptive. The study objective was to test the hypothesis that modulated ICa,L in cRADΔ/Δ mice rescues dilated cardiomyopathy by providing tonic modulated trigger Ca2+. Methods and results Mouse and human models were tested. The muscle lim protein knockout mouse (MLPKO) is a murine model of dilated cardiomyopathy (DCM) and HFrEF. The experimental timeline was to induce cRADΔ/Δ after onset of DCM (2.5 months of age) and follow subjects for up to 1-year. Longitudinal echocardiography and cardiac magnetic resonance imaging (CMR) showed that cRADΔ/Δ intervention rescued systolic function. Patch clamp recordings of isolated cardiomyocytes of MLPKO with cRADΔ/Δ demonstrated augmented LTCC activity, along with rescue of dysfunctional Ca2+ handling and sarcomere function. Bulk RNAseq of hearts demonstrated down-regulated pathological signalling cascades and pro-hypertrophic gene expression which comported with the reduction in eccentric hypertrophy observed with gravimetrics, CMR, and echocardiography. RRAD knockdown effects translate from mouse to human heart. Ventricle slices from HFrEF patients were treated with lentiviral shRNA targeting RRAD and recapitulated the inotropic and lusitropic effects observed in the mouse model of DCM. Conclusion Induction of cardiomyocyte-restricted RAD knockout in MLPKO mice after onset of DCM rescued cardiac dysfunction and attenuated pathological remodelling. cRADΔ/Δ intervention provided positive inotropy and lusitropy and reverted transcriptional signatures towards healthy myocardium. This study introduces targeting myocardial RAD regulation of the LTCC as a novel therapeutic strategy for systolic heart failure.

AB - Aims Heart failure with reduced ejection fraction (HFrEF) is a major health problem. Increasing L-type calcium channel (LTCC) activity deteriorates heart function; however, myocardial RRAD knockout (cRADΔ/Δ) instills tonic modulated LTCC current (ICa,L) that preserves healthy myocardium. Thus, we chose to challenge the dogma that enhanced trigger Ca2+ is maladaptive. The study objective was to test the hypothesis that modulated ICa,L in cRADΔ/Δ mice rescues dilated cardiomyopathy by providing tonic modulated trigger Ca2+. Methods and results Mouse and human models were tested. The muscle lim protein knockout mouse (MLPKO) is a murine model of dilated cardiomyopathy (DCM) and HFrEF. The experimental timeline was to induce cRADΔ/Δ after onset of DCM (2.5 months of age) and follow subjects for up to 1-year. Longitudinal echocardiography and cardiac magnetic resonance imaging (CMR) showed that cRADΔ/Δ intervention rescued systolic function. Patch clamp recordings of isolated cardiomyocytes of MLPKO with cRADΔ/Δ demonstrated augmented LTCC activity, along with rescue of dysfunctional Ca2+ handling and sarcomere function. Bulk RNAseq of hearts demonstrated down-regulated pathological signalling cascades and pro-hypertrophic gene expression which comported with the reduction in eccentric hypertrophy observed with gravimetrics, CMR, and echocardiography. RRAD knockdown effects translate from mouse to human heart. Ventricle slices from HFrEF patients were treated with lentiviral shRNA targeting RRAD and recapitulated the inotropic and lusitropic effects observed in the mouse model of DCM. Conclusion Induction of cardiomyocyte-restricted RAD knockout in MLPKO mice after onset of DCM rescued cardiac dysfunction and attenuated pathological remodelling. cRADΔ/Δ intervention provided positive inotropy and lusitropy and reverted transcriptional signatures towards healthy myocardium. This study introduces targeting myocardial RAD regulation of the LTCC as a novel therapeutic strategy for systolic heart failure.

KW - Dilated cardiomyopathy

KW - Heart failure

KW - L-type calcium channel

KW - Therapeutic strategy

UR - https://www.scopus.com/pages/publications/105022632874

UR - https://www.scopus.com/inward/citedby.url?scp=105022632874&partnerID=8YFLogxK

U2 - 10.1093/cvr/cvaf169

DO - 10.1093/cvr/cvaf169

M3 - Article

C2 - 41032675

AN - SCOPUS:105022632874

SN - 0008-6363

VL - 121

SP - 2204

EP - 2221

JO - Cardiovascular Research

JF - Cardiovascular Research

IS - 14

ER -

RRAD-reduction reveals efficacy of targeting L-type calcium channel regulation for treatment of heart failure

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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