Dataset Information

Oxidized CaMKII causes cardiac sinus node dysfunction in mice.

ABSTRACT: Sinus node dysfunction (SND) is a major public health problem that is associated with sudden cardiac death and requires surgical implantation of artificial pacemakers. However, little is known about the molecular and cellular mechanisms that cause SND. Most SND occurs in the setting of heart failure and hypertension, conditions that are marked by elevated circulating angiotensin II (Ang II) and increased oxidant stress. Here, we show that oxidized calmodulin kinase II (ox-CaMKII) is a biomarker for SND in patients and dogs and a disease determinant in mice. In wild-type mice, Ang II infusion caused sinoatrial nodal (SAN) cell oxidation by activating NADPH oxidase, leading to increased ox-CaMKII, SAN cell apoptosis, and SND. p47-/- mice lacking functional NADPH oxidase and mice with myocardial or SAN-targeted CaMKII inhibition were highly resistant to SAN apoptosis and SND, suggesting that ox-CaMKII-triggered SAN cell death contributed to SND. We developed a computational model of the sinoatrial node that showed that a loss of SAN cells below a critical threshold caused SND by preventing normal impulse formation and propagation. These data provide novel molecular and mechanistic information to understand SND and suggest that targeted CaMKII inhibition may be useful for preventing SND in high-risk patients.

SUBMITTER: Swaminathan PD

PROVIDER: S-EPMC3223923 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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Oxidized CaMKII causes cardiac sinus node dysfunction in mice.

Swaminathan Paari Dominic PD Purohit Anil A Soni Siddarth S Voigt Niels N Singh Madhu V MV Glukhov Alexey V AV Gao Zhan Z He B Julie BJ Luczak Elizabeth D ED Joiner Mei-ling A ML Kutschke William W Yang Jinying J Donahue J Kevin JK Weiss Robert M RM Grumbach Isabella M IM Ogawa Masahiro M Chen Peng-Sheng PS Efimov Igor I Dobrev Dobromir D Mohler Peter J PJ Hund Thomas J TJ Anderson Mark E ME

The Journal of clinical investigation 20110725 8

Sinus node dysfunction (SND) is a major public health problem that is associated with sudden cardiac death and requires surgical implantation of artificial pacemakers. However, little is known about the molecular and cellular mechanisms that cause SND. Most SND occurs in the setting of heart failure and hypertension, conditions that are marked by elevated circulating angiotensin II (Ang II) and increased oxidant stress. Here, we show that oxidized calmodulin kinase II (ox-CaMKII) is a biomarker ...[more]

PMID: 21785215

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Project description:Compromised mitophagy and mitochondrial homeostasis are major contributors for the etiology of cardiac aging, although the precise underlying mechanisms remains elusive. Shank3, a heart-enriched protein, has recently been reported to regulate aging-related neurodegenerative diseases. This study aimed to examine the role of Shank3 in the pathogenesis of cardiac senescence and the possible mechanisms involved. Cardiac-specific conditional Shank3 knockout (Shank3CKO) mice were subjected to natural aging. Mitochondrial function and mitophagy activity were determined in vivo, in mouse hearts and in vitro, in cardiomyocytes. Here, we showed that cardiac Shank3 expression exhibited a gradual increase during the natural progression of the aging, accompanied by overtly decreased mitophagy activity and a decline in cardiac function. Ablation of Shank3 promoted mitophagy, reduced mitochondria-derived superoxide (H2O2 and O2•−) production and apoptosis, and protected against cardiac dysfunction in the aged heart. In an in vitro study, senescent cardiomyocytes treated with D-gal exhibited reduced mitophagy and significantly elevated Shank3 expression. Shank3 knock-down restored mitophagy, leading to increased mitochondrial membrane potential, decreased mitochondrial oxidative stress, and reduced apoptosis in senescent cardiomyocytes, whereas Shank3 overexpression mimicked D-gal-induced mitophagy inhibition and mitochondrial dysfunction in normally cultured cardiomyocytes. Mechanistically, the IP assay revealed that Shank3 directly binds to CaMKII, and this interaction was further increased in the aged heart. Enhanced Shank3/CaMKII binding impedes mitochondrial translocation of CaMKII, resulting in the inhibition of parkin-mediated mitophagy, which ultimately leads to mitochondrial dysfunction and cardiac damage in the aged heart. Our study identified Shank3 as a novel contributor to aging-related cardiac damage. Manipulating Shank3/CaMKII-induced mitophagy inhibition could thus be an optional strategy for therapeutic intervention in clinical aging-related cardiac dysfunctions. Graphical abstract Schematic diagram illustrating that elevated Shank3 in aged heart inhibited parkin-mediated mitophagy by directly binding with CaMKII, which ultimately leads to mitochondrial dysfunction and cardiac damage. Under cardiac aging, upregulated Shank3 binds with CaMKII to impede its mitochondrial translocation, suppressing mitochondrial translocation of Parkin and Parkin-mediated mitophagy. Mitophagy inhibition induced by Shank3/CaMKII binding evokes collapse of mitochondrial membrane potential, promotes mitochondria-derived superoxide production and mitochondria-dependent cardiomyocyte apoptosis, leading to aging-related cardiac dysfunction.Image 1 Highlights • Upregulated Shank3 and inhibited mitophagy activity are responsible for cardiac damage in the aged mice.• Shank3 inhibited mitophagy in the aged hearts by directly binding with CaMKII.• Shank3 ablation suppressed mitochondria-derived oxidative stress and apoptosis by promoting mitophagy.• Targeting mitophagy by regulating Shank3/CaMKII could be a new therapeutic target for aging-related cardiovascular diseases.

Project description:ObjectivesThe role of cardiac arrhythmia in ischaemic stroke is widely studied, but the size of the stroke risk in patients with sinus node dysfunction (SND) with and without atrial fibrillation (AF) is unclear. This systematic review and meta-analysis aimed to compare the risk of stroke and its associated factors in patients with SND with and without AF.DesignA systematic review and meta-analysis was conducted based on the Grading of Recommendations, Assessment, Development and Evaluation approach.Data sourcesPubMed, EMBASE and Cochrane Database were searched until December 2022.Eligibility criteria for selecting studiesStudies that investigate stroke in patients with SND diagnosed with or without AF/atrial flutter.Data extraction and synthesisTwo independent authors screened studies for inclusion and extracted data. Literature quality assessment was performed using the Newcastle-Ottawa Scale and the Cochrane Collaboration Tool. The overall risk of stroke was estimated using the random-effects model. The generic inverse variance method was used to calculate the pooled estimates of stroke-associated factors. We performed a sensitivity analysis using a fixed-effects model.ResultsOf the 929 records retrieved, 6 papers (106 163 patients) met the inclusion criteria. The average yearly stroke incidence in patients with SND was 1.542% (95% CI: 1.334% to 1.749%). The stroke incidence was similar between the isolated SND (1.587%; 95% CI: 1.510% to 1.664%) and non-isolated (SND+AF) (1.660%; 95% CI: 0.705% to 2.615%) groups. AF (HR, 95% CI: 1.53 (1.01 to 2.33)), stroke/transient ischaemia attack/other thrombotic events (HR, 95% CI: 2.54 (1.14 to 5.69)), hypertension (HR, 95% CI: 1.51 (1.11 to 2.07)) and heart failure (HR, 95% CI: 1.41 (1.01 to 1.97)) were associated with stroke in the SND population.ConclusionOur findings suggest that patients with SND carry a similar risk of stroke to those with combined SND and AF. Future studies are needed to investigate whether interventions targeting stroke prevention, such as anticoagulation therapy, can help to prevent stroke in patients with SND.Prospero registration numberCRD42023408436.

Dataset Information

Oxidized CaMKII causes cardiac sinus node dysfunction in mice.

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Oxidized CaMKII causes cardiac sinus node dysfunction in mice.

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