ArticleThe Journal of general physiology2022
Heart failure in mice induces a dysfunction of the sinus node associated with reduced CaMKII signaling.
Article in The Journal of general physiology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 19 citations in OpenAlex.
- cAMP-Activated EPAC Signaling Is an Integral Component of Cardiac Pacemaker Cell Automaticity.Circulation. Arrhythmia and electrophysiology · 2026Article
- Regulation of Pacemaker Current in the Sinoatrial Node by Zonula Occludens-1.bioRxiv : the preprint server for biology · 2026Article
- Wnt/β-catenin pathway induces cardiac dysfunction via AKAP6-mediated RyR2 phosphorylation and sarcoplasmic reticulum calcium leakage.Journal of molecular cell biology · 2025Article
- Aging and sinus node dysfunction: mechanisms and future directions.Clinical science (London, England : 1979) · 2025Review
- CaCells · 2024Review
- HAPLN1 knockdown inhibits heart failure development via activating the PKA signaling pathway.BMC cardiovascular disorders · 2024Article
- Dual effect of cardiac FKBP12.6 overexpression on excitation-contraction coupling and the incidence of ventricular arrhythmia depending on its expression level.Journal of molecular and cellular cardiology · 2024Article
- Mitochondrial dysfunction is a key link involved in the pathogenesis of sick sinus syndrome: a review.Frontiers in cardiovascular medicine · 2024Review
- Ion channel trafficking implications in heart failure.Frontiers in cardiovascular medicine · 2024Review
- The Dysfunction of CaInternational journal of molecular sciences · 2023Review
- Emerging Signaling Regulation of Sinoatrial Node Dysfunction.Current cardiology reports · 2023Review
- The role of P21-activated kinase (Pak1) in sinus node function.Journal of molecular and cellular cardiology · 2023Article
- Synergy between Membrane Currents Prevents Severe Bradycardia in Mouse Sinoatrial Node Tissue.International journal of molecular sciences · 2023Article
- Review
- The Inferior Sinoatrial Node Suffers the Most During Heart Failure.JACC. Clinical electrophysiology · 2022Article
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Authors and funding
7 authors at 2 institutions in 2 countries.
Funding
Abstract
Dysfunction of the sinoatrial node (SAN), the natural heart pacemaker, is common in heart failure (HF) patients. SAN spontaneous activity relies on various ion currents in the plasma membrane (voltage clock), but intracellular Ca2+ ([Ca2+]i) release via ryanodine receptor 2 (RYR2; Ca2+ clock) plays an important synergetic role. Whereas remodeling of voltage-clock components has been revealed in HF, less is known about possible alterations to the Ca2+ clock. Here, we analyzed [Ca2+]i handling in SAN from a mouse HF model after transverse aortic constriction (TAC) and compared it with sham-operated animals. ECG data from awake animals showed slower heart rate in HF mice upon autonomic nervous system blockade, indicating intrinsic sinus node dysfunction. Confocal microscopy analyses of SAN cells within whole tissue showed slower and less frequent [Ca2+]i transients in HF. This correlated with fewer and smaller spontaneous Ca2+ sparks in HF SAN cells, which associated with lower RYR2 protein expression level and reduced phosphorylation at the CaMKII site. Moreover, PLB phosphorylation at the CaMKII site was also decreased in HF, which could lead to reduced sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) function and lower sarcoplasmic reticulum Ca2+ content, further depressing the Ca2+ clock. The inhibition of CaMKII with KN93 slowed [Ca2+]i transient rate in both groups, but this effect was smaller in HF SAN, consistent with less CaMKII activation. In conclusion, our data uncover that the mechanism of intrinsic pacemaker dysfunction in HF involves reduced CaMKII activation.
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