ArticleJournal of molecular and cellular cardiology2010
Role of mitochondrial dysfunction in cardiac glycoside toxicity.
Article in Journal of molecular and cellular cardiology, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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Who cites it
46 citing papers in PubMed, 91 citations in OpenAlex.
- Mechano-energetic uncoupling in heart failure.Nature reviews. Cardiology · 2025Review
- Prognostic impact of diabetes in chronic and acute heart failure.Heart failure reviews · 2023Review
- Changes in cellular CaThe Journal of physiology · 2023Article
- Mitochondrial Effects of Common Cardiovascular Medications: The Good, the Bad and the Mixed.International journal of molecular sciences · 2022Review
- Mitochondria as Therapeutic Targets in Heart Failure.Current heart failure reports · 2022Review
- Genetic Ablation of Na,K-ATPase α4 Results in Sperm Energetic Defects.Frontiers in cell and developmental biology · 2022Article
- Cardiomyocyte NaBasic research in cardiology · 2021Article
- Estimating ectopic beat probability with simplified statistical models that account for experimental uncertainty.PLoS computational biology · 2021Article
- MCU Overexpression Rescues Inotropy and Reverses Heart Failure by Reducing SR CaCirculation research · 2021Article
- Mitochondrial CaJournal of molecular and cellular cardiology · 2021Review
- Intracellular sodium elevation reprograms cardiac metabolism.Nature communications · 2020Article
- The cardiolipin-binding peptide elamipretide mitigates fragmentation of cristae networks following cardiac ischemia reperfusion in rats.Communications biology · 2020Article
- Treatments targeting inotropy.European heart journal · 2019Article
- Unbalance Between Sarcoplasmic Reticulum CaFrontiers in physiology · 2019Review
- Pharmacological Modulation of Mitochondrial CaFrontiers in physiology · 2018Article
- The Role of Sodium in Diabetic Cardiomyopathy.Frontiers in physiology · 2018Review
- Estimating the probabilities of rare arrhythmic events in multiscale computational models of cardiac cells and tissue.PLoS computational biology · 2017Article
- Targeting Mitochondrial Calcium Handling and Reactive Oxygen Species in Heart Failure.Current heart failure reports · 2017Review
- Expert consensus document: Mitochondrial function as a therapeutic target in heart failure.Nature reviews. Cardiology · 2017Review
- Impaired cardiac and skeletal muscle bioenergetics in children, adolescents, and young adults with Barth syndrome.Physiological reports · 2017Article
Corrections and comments
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
Abstract
Cardiac glycosides, which inhibit the plasma membrane Na(+) pump, are one of the four categories of drug recommended for routine use to treat heart failure, yet their therapeutic window is limited by toxic effects. Elevated cytoplasmic Na(+) ([Na(+)](i)) compromises mitochondrial energetics and redox balance by blunting mitochondrial Ca(2+) ([Ca(2+)](m)) accumulation, and this impairment can be prevented by enhancing [Ca(2+)](m). Here, we investigate whether this effect underlies the toxicity and arrhythmogenic effects of cardiac glycosides and if these effects can be prevented by suppressing mitochondrial Ca(2+) efflux, via inhibition of the mitochondrial Na(+)/Ca(2+) exchanger (mNCE). In isolated cardiomyocytes, ouabain elevated [Na(+)](i) in a dose-dependent way, blunted [Ca(2+)](m) accumulation, decreased the NADH/NAD+redox potential, and increased reactive oxygen species (ROS). Concomitant treatment with the mNCE inhibitor CGP-37157 ameliorated these effects. CGP-37157 also attenuated ouabain-induced cellular Ca(2+) overload and prevented delayed afterdepolarizations (DADs). In isolated perfused hearts, ouabain's positive effects on contractility and respiration were markedly potentiated by CGP-37157, as were those mediated by β-adrenergic stimulation. Furthermore, CGP-37157 inhibited the arrhythmogenic effects of ouabain in both isolated perfused hearts and in vivo. The findings reveal the mechanism behind cardiac glycoside toxicity and show that improving mitochondrial Ca(2+) retention by mNCE inhibition can mitigate these effects, particularly with respect to the suppression of Ca(2+)-triggered arrhythmias, while enhancing positive inotropic actions. These results suggest a novel strategy for the treatment of heart failure.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.