ArticleHeart rhythm2012
CaMKII inhibition rescues proarrhythmic phenotypes in the model of human ankyrin-B syndrome.
Article in Heart rhythm, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed.
- Reappraisal ofReviews in cardiovascular medicine · 2025Review
- Loss of protein phosphatase 2A regulatory subunitFrontiers in cardiovascular medicine · 2024Article
- Mouse models of spontaneous atrial fibrillation.Mammalian genome : official journal of the International Mammalian Genome Society · 2023Review
- CaMKII as a Therapeutic Target in Cardiovascular Disease.Annual review of pharmacology and toxicology · 2023Review
- Role of CaArchives of toxicology · 2023Review
- Mechanisms underlying the role of ankyrin-B in cardiac and neurological health and disease.Frontiers in cardiovascular medicine · 2022Review
- Human ankyrins and their contribution to disease biology: An update.Journal of biosciences · 2020Review
- Protein Phosphatase 2A Regulates Cardiac NaCirculation research · 2019Article
- Ankyrin-B Q1283H Variant Linked to Arrhythmias Via Loss of Local Protein Phosphatase 2A Activity Causes Ryanodine Receptor Hyperphosphorylation.Circulation · 2018Article
- Spectrin-based pathways underlying electrical and mechanical dysfunction in cardiac disease.Expert review of cardiovascular therapy · 2018Article
- The evolving role of ankyrin-B in cardiovascular disease.Heart rhythm · 2017Review
- CaMKII: The molecular villain that aggravates cardiovascular disease.Experimental and therapeutic medicine · 2017Article
- Ankyrins and Spectrins in Cardiovascular Biology and Disease.Frontiers in physiology · 2017Review
- Murine Electrophysiological Models of Cardiac Arrhythmogenesis.Physiological reviews · 2017Review
- The Arrhythmogenic Calmodulin Mutation D129G Dysregulates Cell Growth, Calmodulin-dependent Kinase II Activity, and Cardiac Function in Zebrafish.The Journal of biological chemistry · 2016Article
- Roles and regulation of protein phosphatase 2A (PP2A) in the heart.Journal of molecular and cellular cardiology · 2016Review
- Regulation of sarcoplasmic reticulum CaJournal of molecular and cellular cardiology · 2016Review
- Elevated local [Ca2+] and CaMKII promote spontaneous Ca2+ release in ankyrin-B-deficient hearts.Cardiovascular research · 2016Article
- Atrial remodelling in atrial fibrillation: CaMKII as a nodal proarrhythmic signal.Cardiovascular research · 2016Review
- Voltage-Gated Sodium Channel Phosphorylation at Ser571 Regulates Late Current, Arrhythmia, and Cardiac Function In Vivo.Circulation · 2015Article
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13 authors.
Funding
Abstract
backgroundCardiovascular disease is a leading cause of death worldwide. Arrhythmias are associated with significant morbidity and mortality related to cardiovascular disease. Recent work illustrates that many cardiac arrhythmias are initiated by a pathologic imbalance between kinase and phosphatase activities in excitable cardiomyocytes.
objectiveTo test the relationship between myocyte kinase/phosphatase imbalance and cellular and whole animal arrhythmia phenotypes associated with ankyrin-B cardiac syndrome.
methodsBy using a combination of biochemical, electrophysiological, and in vivo approaches, we tested the ability of calcium/calmodulin-dependent kinase (CaMKII) inhibition to rescue imbalance in kinase/phosphatase pathways associated with human ankyrin-B-associated cardiac arrhythmia.
resultsThe cardiac ryanodine receptor (RyR(2)), a validated target of kinase/phosphatase regulation in myocytes, displays abnormal CaMKII-dependent phosphorylation (pS2814 hyperphosphorylation) in ankyrin-B(+/-) heart. Notably, RyR(2) dysregulation is rescued in myocytes from ankyrin-B(+/-) mice overexpressing a potent CaMKII-inhibitory peptide (AC3I), and aberrant RyR(2) open probability observed in ankyrin-B(+/-) hearts is normalized by treatment with the CaMKII inhibitor KN-93. CaMKII inhibition is sufficient to rescue abnormalities in ankyrin-B(+/-) myocyte electrical dysfunction including cellular afterdepolarizations, and significantly blunts whole animal cardiac arrhythmias and sudden death in response to elevated sympathetic tone.
conclusionsThese findings illustrate the complexity of the molecular components involved in human arrhythmia and define regulatory elements of the ankyrin-B pathway in pathophysiology. Furthermore, the findings illustrate the potential impact of CaMKII inhibition in the treatment of a congenital form of human cardiac arrhythmia.
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