ArticleThe Journal of physiology2010
Sodium accumulation promotes diastolic dysfunction in end-stage heart failure following Serca2 knockout.
Article in The Journal of physiology, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 60 papers.
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Who cites it
60 citing papers in PubMed, 94 citations in OpenAlex.
- Sildenafil and diastolic dysfunction after acute myocardial infarction trial: rationale and design.Clinical cardiology · 2013Trial
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- Epigenetic Mechanisms in Heart Diseases.Reviews in cardiovascular medicine · 2025Review
- TRPV2 mediates stress resilience in mouse cardiomyocytes.Communications biology · 2025Article
- Altered endoplasmic reticulum calcium loading in human PLN-R14del cardiomyopathy.Frontiers in cell and developmental biology · 2025Article
- Myocardial SERCA2 Protects Against Cardiac Damage and Dysfunction Caused by Inhaled Bromine.The Journal of pharmacology and experimental therapeutics · 2024Article
- Myofilament-based physiological regulatory compensation preserves diastolic function in failing hearts with severe Ca2+ handling deficits.JCI insight · 2024Article
- Qifu Yixin Formula Improves Heart Failure by Enhancing β-Arrestin2 Mediated the SUMOylation of SERCA2a.Drug design, development and therapy · 2024Article
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- Targeting calcium regulators as therapy for heart failure: focus on the sarcoplasmic reticulum Ca-ATPase pump.Frontiers in cardiovascular medicine · 2023Review
- Structure-function relationships and modifications of cardiac sarcoplasmic reticulum Ca2+-transport.Physiological research · 2021Review
- Article
- Sarcoplasmic Reticulum Calcium Release Is Required for Arrhythmogenesis in the Mouse.Frontiers in physiology · 2021Article
- Predominance of Heart Failure With Preserved Ejection Fraction in Postmenopausal Women: Intra- and Extra-Cardiomyocyte Maladaptive Alterations Scaffolded by Estrogen Deficiency.Frontiers in cell and developmental biology · 2021Review
- Afterdepolarizations and abnormal calcium handling in atrial myocytes with modulated SERCA uptake: a sensitivity analysis of calcium handling channels.Philosophical transactions. Series A, Mathematical, physical, and engineering sciences · 2020Article
- Changes in cellular CaThe Journal of physiology · 2020Article
- Hypokalemia Promotes Arrhythmia by Distinct Mechanisms in Atrial and Ventricular Myocytes.Circulation research · 2020Article
- The Control of Diastolic Calcium in the Heart: Basic Mechanisms and Functional Implications.Circulation research · 2020Review
- Targeting CaFrontiers in physiology · 2020Review
- Late Sodium Current Inhibitors as Potential Antiarrhythmic Agents.Frontiers in pharmacology · 2020Review
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Authors and funding
11 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Alterations in trans-sarcolemmal and sarcoplasmic reticulum (SR) Ca(2+) fluxes may contribute to impaired cardiomyocyte contraction and relaxation in heart failure. We investigated the mechanisms underlying heart failure progression in mice with conditional, cardiomyocyte-specific excision of the SR Ca(2+)-ATPase (SERCA) gene. At 4 weeks following gene deletion (4-week KO) cardiac function remained near normal values. However, end-stage heart failure developed by 7 weeks (7-week KO) as systolic and diastolic performance declined. Contractions in isolated myocytes were reduced between 4- and 7-week KO, and relaxation was slowed. Ca(2+) transients were similarly altered. Reduction in Ca(2+) transient magnitude resulted from complete loss of SR Ca(2+) release between 4- and 7-week KO, due to loss of a small remaining pool of SERCA2. Declining SR Ca(2+) release was partly offset by increased L-type Ca(2+) current, which was facilitated by AP prolongation in 7-week KO. Ca(2+) entry via reverse-mode Na(+)-Ca(2+) exchange (NCX) was also enhanced. Up-regulation of NCX and plasma membrane Ca(2+)-ATPase increased Ca(2+) extrusion rates in 4-week KO. Diastolic dysfunction in 7-week KO resulted from further SERCA2 loss, but also impaired NCX-mediated Ca(2+) extrusion following Na(+) accumulation. Reduced Na(+)-K(+)-ATPase activity contributed to the Na(+) gain. Normalizing [Na(+)] by dialysis increased the Ca(2+) decline rate in 7-week KO beyond 4-week values. Thus, while SERCA2 loss promotes both systolic and diastolic dysfunction, Na(+) accumulation additionally impairs relaxation in this model. Our observations indicate that if cytosolic Na(+) gain is prevented, up-regulated Ca(2+) extrusion mechanisms can maintain near-normal diastolic function in the absence of SERCA2.
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