ArticleCirculation research2011
Reactive oxygen species-activated Ca/calmodulin kinase IIδ is required for late I(Na) augmentation leading to cellular Na and Ca overload.
Article in Circulation research, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 175 papers, 1 of them a synthesis that pooled it.
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Who cites it
175 citing papers in PubMed, 1 synthesis or guideline pooled it, 270 citations in OpenAlex.
- The role of the PM2.5-associated metals in pathogenesis of child Mycoplasma Pneumoniae infections: a systematic review.Environmental science and pollution research international · 2016Pooled it
- A Computational Model of Oxidative Stress in a Human Ventricular Myocyte.bioRxiv : the preprint server for biology · 2026Article
- Exploring the role of CaMKII in exercise-induced cardioprotection.Human cell · 2026Review
- Obstructive Sleep Apnea and Arrhythmia: A Narrative Review of Arrhythmogenic Mechanisms.Diagnostics (Basel, Switzerland) · 2026Review
- SGLT2 Inhibitors in Hypertrophic Cardiomyopathy: Emerging Evidence and Putative Mechanisms.Biomolecules · 2026Review
- Article
- Impact of diabetes mellitus on mortality and atrial fibrillation in hypertrophic cardiomyopathy: A systematic review and meta-analysis.World journal of diabetes · 2025Article
- Metabolic-Electrophysiological Coupling in Heart Failure: from Bidirectional Decoupling to Therapeutic Recoupling.Current heart failure reports · 2025Review
- Mechanisms underlying atrial fibrillation in chronic kidney disease.Journal of molecular and cellular cardiology · 2025Review
- Retinoic acid signaling and metabolism in heart failure.American journal of physiology. Heart and circulatory physiology · 2025Review
- Ion channel traffic jams: the significance of trafficking deficiency in long QT syndrome.Cell discovery · 2025Review
- Empagliflozin attenuates doxorubicin-impaired cardiac contractility by suppressing reactive oxygen species in isolated myocytes.Molecular and cellular biochemistry · 2024Article
- Cardiac monoamine oxidase-A inhibition protects against catecholamine-induced ventricular arrhythmias via enhanced diastolic calcium control.Cardiovascular research · 2024Article
- CaMKIIδ-dependent dysregulation of atrial NaFrontiers in pharmacology · 2024Article
- The inotropic and arrhythmogenic effects of acutely increased late IFrontiers in cardiovascular medicine · 2024Article
- A multiscale predictive digital twin for neurocardiac modulation.The Journal of physiology · 2023Article
- SGLT2 inhibitors: role in protective reprogramming of cardiac nutrient transport and metabolism.Nature reviews. Cardiology · 2023Review
- Mechano-energetic uncoupling in hypertrophic cardiomyopathy: Pathophysiological mechanisms and therapeutic opportunities.Journal of molecular and cellular cardiology plus · 2023Review
- An integrative review of nonobvious puzzles of cellular and molecular cardiooncology.Cellular & molecular biology letters · 2023Review
- Mitochondrial connexin43 and mitochondrial KPflugers Archiv : European journal of physiology · 2023Article
115 more citing papers are in PubMed but not listed here.
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Authors and funding
12 authors at 3 institutions in 2 countries.
Funding
Abstract
rationaleIn heart failure Ca/calmodulin kinase (CaMK)II expression and reactive oxygen species (ROS) are increased. Both ROS and CaMKII can increase late I(Na) leading to intracellular Na accumulation and arrhythmias. It has been shown that ROS can activate CaMKII via oxidation.
objectiveWe tested whether CaMKIIδ is required for ROS-dependent late I(Na) regulation and whether ROS-induced Ca released from the sarcoplasmic reticulum (SR) is involved. METHODS AND
results40 μmol/L H(2)O(2) significantly increased CaMKII oxidation and autophosphorylation in permeabilized rabbit cardiomyocytes. Without free [Ca](i) (5 mmol/L BAPTA/1 mmol/L Br(2)-BAPTA) or after SR depletion (caffeine 10 mmol/L, thapsigargin 5 μmol/L), the H(2)O(2)-dependent CaMKII oxidation and autophosphorylation was abolished. H(2)O(2) significantly increased SR Ca spark frequency (confocal microscopy) but reduced SR Ca load. In wild-type (WT) mouse myocytes, H(2)O(2) increased late I(Na) (whole cell patch-clamp). This increase was abolished in CaMKIIδ(-/-) myocytes. H(2)O(2)-induced [Na](i) and [Ca](i) accumulation (SBFI [sodium-binding benzofuran isophthalate] and Indo-1 epifluorescence) was significantly slowed in CaMKIIδ(-/-) myocytes (versus WT). CaMKIIδ(-/-) myocytes developed significantly less H(2)O(2)-induced arrhythmias and were more resistant to hypercontracture. Opposite results (increased late I(Na), [Na](i) and [Ca](i) accumulation) were obtained by overexpression of CaMKIIδ in rabbit myocytes (adenoviral gene transfer) reversible with CaMKII inhibition (10 μmol/L KN93 or 0.1 μmol/L AIP [autocamtide 2-related inhibitory peptide]).
conclusionsFree [Ca](i) and a functional SR are required for ROS activation of CaMKII. ROS-activated CaMKIIδ enhances late I(Na), which may lead to cellular Na and Ca overload. This may be of relevance in hear failure, where enhanced ROS production meets increased CaMKII expression.
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