ArticleJournal of molecular and cellular cardiology2014
Cell-based delivery of dATP via gap junctions enhances cardiac contractility.
Article in Journal of molecular and cellular cardiology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 23 citations in OpenAlex.
- NetSci: A Library for High Performance Biomolecular Simulation Network Analysis Computation.Journal of chemical information and modeling · 2024Article
- Multiscale modeling shows how 2'-deoxy-ATP rescues ventricular function in heart failure.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Multiscale computational modeling of the effects of 2'-deoxy-ATP on cardiac muscle calcium handling.Journal of applied physics · 2023Article
- dATP elevation induces myocardial metabolic remodeling to support improved cardiac function.Journal of molecular and cellular cardiology · 2023Article
- Cardiac myosin contraction and mechanotransduction in health and disease.The Journal of biological chemistry · 2021Review
- Modulating the tension-time integral of the cardiac twitch prevents dilated cardiomyopathy in murine hearts.JCI insight · 2020Article
- Gene Therapy Rescues Cardiac Dysfunction in Duchenne Muscular Dystrophy Mice by Elevating Cardiomyocyte Deoxy-Adenosine Triphosphate.JACC. Basic to translational science · 2019Article
- Re-Defining Stem Cell-Cardiomyocyte Interactions: Focusing on the Paracrine Effector Approach.Journal of stem cells & regenerative medicine · 2018Article
- Molecular mechanisms underlying deoxy-ADP.Pi activation of pre-powerstroke myosin.Protein science : a publication of the Protein Society · 2017Article
- Cardiac Myosin Activation with Gene Therapy Produces Sustained Inotropic Effects and May Treat Heart Failure with Reduced Ejection Fraction.Handbook of experimental pharmacology · 2017Review
- Translation of Cardiac Myosin Activation with 2-deoxy-ATP to Treat Heart Failure via an Experimental Ribonucleotide Reductase-Based Gene Therapy.JACC. Basic to translational science · 2016Article
- AAV6-mediated Cardiac-specific Overexpression of Ribonucleotide Reductase Enhances Myocardial Contractility.Molecular therapy : the journal of the American Society of Gene Therapy · 2016Article
- Molecular effects of the myosin activator omecamtiv mecarbil on contractile properties of skinned myocardium lacking cardiac myosin binding protein-C.Journal of molecular and cellular cardiology · 2015Article
- Ribonucleotide reductase-mediated increase in dATP improves cardiac performance via myosin activation in a large animal model of heart failure.European journal of heart failure · 2015Article
- Modelling sarcomeric cardiomyopathies in the dish: from human heart samples to iPSC cardiomyocytes.Cardiovascular research · 2015Review
- 2-Deoxy adenosine triphosphate improves contraction in human end-stage heart failure.Journal of molecular and cellular cardiology · 2015Article
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
The transplantation of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) is a promising strategy to treat myocardial infarction and reverse heart failure, but to date the contractile benefit in most studies remains modest. We have previously shown that the nucleotide 2-deoxyadenosine triphosphate (dATP) can substitute for ATP as the energy substrate for cardiac myosin, and increasing cellular dATP content by globally overexpressing ribonucleotide reductase (R1R2) can dramatically enhance cardiac contractility. Because dATP is a small molecule, we hypothesized that it would diffuse readily between cells via gap junctions and enhance the contractility of neighboring coupled wild type cells. To test this hypothesis, we performed studies with the goals of (1) validating gap junction-mediated dATP transfer in vitro and (2) investigating the use of R1R2-overexpressing hPSC-CMs in vivo as a novel strategy to increase cardiac function. We first performed intracellular dye transfer studies using dATP conjugated to fluorescein and demonstrated rapid gap junction-mediated transfer between cardiomyocytes. We then cocultured wild type cardiomyocytes with either cardiomyocytes or fibroblasts overexpressing R1R2 and saw more than a twofold increase in the extent and rate of contraction of wild type cardiomyocytes. Finally, we transplanted hPSC-CMs overexpressing R1R2 into healthy uninjured rat hearts and noted an increase in fractional shortening from 41±4% to 53±5% just five days after cell transplantation. These findings demonstrate that dATP is an inotropic factor that spreads between cells via gap junctions. Our data suggest that transplantation of dATP-producing hPSC-CMs could significantly increase the effectiveness of cardiac cell therapy.
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