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Citations to this article

Cardiac resynchronization sensitizes the sarcomere to calcium by reactivating GSK-3β
Jonathan A. Kirk, … , Jennifer Van Eyk, David A. Kass
Jonathan A. Kirk, … , Jennifer Van Eyk, David A. Kass
Published December 2, 2013
Citation Information: J Clin Invest. 2014;124(1):129-139. https://doi.org/10.1172/JCI69253.
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Research Article Cardiology Article has an altmetric score of 69

Cardiac resynchronization sensitizes the sarcomere to calcium by reactivating GSK-3β

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Abstract

Cardiac resynchronization therapy (CRT), the application of biventricular stimulation to correct discoordinate contraction, is the only heart failure treatment that enhances acute and chronic systolic function, increases cardiac work, and reduces mortality. Resting myocyte function also increases after CRT despite only modest improvement in calcium transients, suggesting that CRT may enhance myofilament calcium responsiveness. To test this hypothesis, we examined adult dogs subjected to tachypacing-induced heart failure for 6 weeks, concurrent with ventricular dyssynchrony (HFdys) or CRT. Myofilament force-calcium relationships were measured in skinned trabeculae and/or myocytes. Compared with control, maximal calcium-activated force and calcium sensitivity declined globally in HFdys; however, CRT restored both. Phosphatase PP1 induced calcium desensitization in control and CRT-treated cells, while HFdys cells were unaffected, implying that CRT enhances myofilament phosphorylation. Proteomics revealed phosphorylation sites on Z-disk and M-band proteins, which were predicted to be targets of glycogen synthase kinase-3β (GSK-3β). We found that GSK-3β was deactivated in HFdys and reactivated by CRT. Mass spectrometry of myofilament proteins from HFdys animals incubated with GSK-3β confirmed GSK-3β–dependent phosphorylation at many of the same sites observed with CRT. GSK-3β restored calcium sensitivity in HFdys, but did not affect control or CRT cells. These data indicate that CRT improves calcium responsiveness of myofilaments following HFdys through GSK-3β reactivation, identifying a therapeutic approach to enhancing contractile function.

Authors

Jonathan A. Kirk, Ronald J. Holewinski, Viola Kooij, Giulio Agnetti, Richard S. Tunin, Namthip Witayavanitkul, Pieter P. de Tombe, Wei Dong Gao, Jennifer Van Eyk, David A. Kass

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Citations to this article (44)

Title and authors Publication Year
Concepts of Cardiac Dyssynchrony and Dynamic Approach
Catrina BI, Batar F, Manitiu I, Prodan L, Tanasescu C, Filip T
Diagnostics 2024
Determinação dos Níveis Séricos de Glicogênio Sintase 3 Beta em Pacientes com Insuficiência Cardíaca, um Novo Marcador para Diagnóstico e Definição da Gravidade da Doença?
Altunbas G, Kaplan M, Duzen V, Kaya EE, Gokdeniz HG, Taysi S
Arquivos Brasileiros de Cardiologia 2024
GSK-3 at the heart of cardiometabolic diseases: Isoform-specific targeting is critical to therapeutic benefit
Umbarkar P, Ruiz Ramirez SY, Toro Cora A, Tousif S, Lal H
2023
Dyssynchrony and resynchronization in heart failure—effects on regional and global gene expression in a murine pacemaker model
Ståhlberg M, Rullman E, Pernow J, Nakagawa R, Nordin H, Braunschweig F, Ljung K
2023
miR-455-5p promotes pathological cardiac remodeling via suppression of PRMT1-mediated Notch signaling pathway
Cai S, Chang J, Su M, Wei Y, Sun H, Chen C, Yiu KH
Cellular and Molecular Life Sciences 2023
GSK-3β Localizes to the Cardiac Z-Disc to Maintain Length Dependent Activation
M Stachowski-Doll, M Papadaki, T Martin, W Ma, H Gong, S Shao, S Shen, N Muntu, M Kumar, E Perez, J Martin, C Moravec, S Sadayappan, S Campbell, T Irving, J Kirk
Circulation research 2022
Dyssynchronous Heart Failure: A Clinical Review.
Dikdan SJ, Co ML, Pavri BB
Current Cardiology Reports 2022
Cardiomyocyte contractile impairment in heart failure results from reduced BAG3-mediated sarcomeric protein turnover
TG Martin, VD Myers, P Dubey, S Dubey, E Perez, CS Moravec, MS Willis, AM Feldman, JA Kirk
Nature Communications 2021
BAG3 expression and sarcomere localization in the human heart are linked to HSF-1 and are differentially affected by sex and disease
TG Martin, S Tawfik, CS Moravec, TR Pak, JA Kirk
American journal of physiology. Heart and circulatory physiology 2021
PDE1 Inhibition Modulates Ca v 1.2 Channel to Stimulate Cardiomyocyte Contraction
GK Muller, J Song, V Jani, Y Wu, T Liu, WP Jeffreys, B O'Rourke, ME Anderson, DA Kass
Circulation research 2021
Glycation of ryanodine receptor in circulating lymphocytes predicts the response to cardiac resynchronization therapy
J Gambardella, S Jankauskas, S D'Ascia, C Sardu, A Matarese, F Minicucci, P Mone, G Santulli
The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation 2021
Regional protein expression changes within the left ventricle in a mouse model of dyssynchronous and resynchronized heart failure
H Nordin, R Nakagawa, M Wallin, J Pernow, DA Kass, M Ståhlberg
ESC Heart Failure 2020
Cardiomyocyte-GSK-3α promotes mPTP opening and heart failure in mice with chronic pressure overload
F Ahmad, AP Singh, D Tomar, M Rahmani, Q Zhang, JR Woodgett, DG Tilley, H Lal, T Force
Journal of Molecular and Cellular Cardiology 2019
Chronic Atrial and Ventricular Pacing in the Mouse: Application to Model Cardiac Dyssynchrony and Resynchronization in Heart Failure
M Ståhlberg, R Nakagawa, D Bedja, G Zhu, BL Lin, A Saberi, DI Lee, DA Kass
Circulation. Heart failure 2019
The mechanical effects of CRT promoting autophagy via mitochondrial calcium uniporter down‐regulation and mitochondrial dynamics alteration
Z Yu, X Gong, Y Yu, M Li, Y Liang, S Qin, Z Fulati, N Zhou, X Shu, Z Nie, S Dai, X Chen, J Wang, R Chen, Y Su, J Ge
Journal of Cellular and Molecular Medicine 2019
Cardiac Resynchronisation Therapy and Cellular Bioenergetics: Effects Beyond Chamber Mechanics
CK Antoniou, P Manolakou, N Magkas, K Konstantinou, C Chrysohoou, P Dilaveris, KA Gatzoulis, D Tousoulis
European Cardiology Review 2019
Diabetes with heart failure increases methylglyoxal modifications in the sarcomere which inhibit function
Maria Papadaki, Ronald Holewinski, Samantha Previs, Thomas Martin, Nikolai Smolin, Marisa Stachowski, Amy Li, Cheavar Blair, Christine Moravec, Jennifer van Eyk, Kenneth Campbell, David Warshaw, Seth Robia, Jonathan Kirk
JCI Insight 2018
Protein S -Nitrosylation Controls Glycogen Synthase Kinase 3β Function Independent of Its Phosphorylation State
SB Wang, V Venkatraman, EL Crowgey, T Liu, Z Fu, R Holewinski, M Ranek, DA Kass, B ORourke, JE Eyk
Circulation research 2018
Temperature-sensitive sarcomeric protein post-translational modifications revealed by top-down proteomics
W Cai, ZL Hite, B Lyu, Z Wu, Z Lin, ZR Gregorich, AE Messer, SJ McIlwain, SB Marston, T Kohmoto, Y Ge
Journal of Molecular and Cellular Cardiology 2018
Phospho-Proteomic Analysis of Cardiac Dyssynchrony and Resynchronization Therapy
MJ Stachowski, RJ Holewinski, E Grote, V Venkatraman, JE Eyk, JA Kirk
PROTEOMICS 2018
Unraveling obscurins in heart disease
A Grogan, A Kontrogianni-Konstantopoulos
Pflügers Archiv - European Journal of Physiology 2018
Right Ventricular Myofilament Functional Differences in Humans With Systemic Sclerosis–Associated Versus Idiopathic Pulmonary Arterial Hypertension
S Hsu, KM Kokkonen-Simon, JA Kirk, TM Kolb, RL Damico, SC Mathai, M Mukherjee, AA Shah, FM Wigley, KB Margulies, PM Hassoun, MK Halushka, RJ Tedford, DA Kass
Circulation 2018
Kinase inhibitor screening using artificial neural networks and engineered cardiac biowires
G Conant, S Ahadian, Y Zhao, M Radisic
Scientific Reports 2017
WNT Signaling in Cardiac and Vascular Disease
S Foulquier, EP Daskalopoulos, G Lluri, KC Hermans, A Deb, WM Blankesteijn, MC Michel
Pharmacological reviews 2017
Prominent differences in left ventricular performance and myocardial properties between right ventricular and left ventricular-based pacing modes in rats
W Mulla, S Etzion, S Elyagon, R Gillis, M Murninkas, Y Konstantino, I Mannhardt, T Eschenhagen, N Liel-Cohen, Y Etzion
Scientific Reports 2017
Mast cells regulate myofilament calcium sensitization and heart function after myocardial infarction
A Ngkelo, A Richart, JA Kirk, P Bonnin, J Vilar, M Lemitre, P Marck, M Branchereau, SL Gall, N Renault, C Guerin, MJ Ranek, A Kervadec, L Danelli, G Gautier, U Blank, P Launay, E Camerer, P Bruneval, P Menasche, C Heymes, E Luche, L Casteilla, B Cousin, HR Rodewald, DA Kass, JS Silvestre
Journal of Experimental Medicine 2016
Assessing Cardiac Metabolism: A Scientific Statement From the American Heart Association
H Taegtmeyer, ME Young, GD Lopaschuk, ED Abel, H Brunengraber, V Darley-Usmar, CD Rosiers, R Gerszten, JF Glatz, JL Griffin, RJ Gropler, HG Holzhuetter, JR Kizer, ED Lewandowski, CR Malloy, S Neubauer, LR Peterson, MA Portman, FA Recchia, JE van Eyk, TJ Wang
Circulation research 2016
Insulin Signaling in Bupivacaine-induced Cardiac Toxicity: Sensitization during Recovery and Potentiation by Lipid Emulsion
MR Fettiplace, K Kowal, R Ripper, A Young, K Lis, I Rubinstein, M Bonini, R Minshall, G Weinberg
Anesthesiology 2016
Quantitative Proteomics by Mass Spectrometry
S Sechi
Quantitative Proteomics by Mass Spectrometry 2016
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G Santulli, G Iaccarino
Maturitas 2016
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E Nemutlu, S Zhang, YZ Xu, A Terzic, L Zhong, PD Dzeja, YM Cha
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Pacemaker-induced transient asynchrony suppresses heart failure progression
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Phosphodiesterase 9A controls nitric-oxide-independent cGMP and hypertrophic heart disease
DI Lee, G Zhu, T Sasaki, GS Cho, N Hamdani, R Holewinski, SH Jo, T Danner, M Zhang, PP Rainer, D Bedja, JA Kirk, MJ Ranek, WR Dostmann, C Kwon, KB Margulies, JE van Eyk, WJ Paulus, E Takimoto, DA Kass
Nature 2015
Removal of Abnormal Myofilament O -GlcNAcylation Restores Ca 2+ Sensitivity in Diabetic Cardiac Muscle
GA Ramirez-Correa, J Ma, C Slawson, Q Zeidan, NS Lugo-Fagundo, M Xu, X Shen, WD Gao, V Caceres, K Chakir, L DeVine, RN Cole, L Marchionni, N Paolocci, GW Hart, AM Murphy
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Citrullination of myofilament proteins in heart failure
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The GSK-3 Family as Therapeutic Target for Myocardial Diseases
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