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Updated: May 6, 2026
Isolation, Culture, and Functional Characterization of Adult Mouse Cardiomyoctyes
Published on: September 25, 2013
Oxidized CaMKII causes cardiac sinus node dysfunction in mice
Paari Dominic Swaminathan1, Anil Purohit, Siddarth Soni
1Division of Cardiovascular Medicine, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.
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.
Insights
Oxidized calmodulin kinase II (ox-CaMKII) is a biomarker and driver of sinus node dysfunction (SND). Inhibiting ox-CaMKII may prevent SND, a condition linked to sudden cardiac death.
Area of Science:
- Cardiology
- Molecular Biology
- Biochemistry
Background:
- Sinus node dysfunction (SND) is a significant public health concern linked to sudden cardiac death.
- SND often occurs with heart failure and hypertension, conditions associated with elevated angiotensin II (Ang II) and oxidative stress.
- The precise molecular mechanisms underlying SND remain poorly understood.
Purpose of the Study:
- To investigate the role of oxidized calmodulin kinase II (ox-CaMKII) in the pathogenesis of SND.
- To identify potential therapeutic targets for preventing SND.
Main Methods:
- Utilized patient and animal models (dogs and mice) to study SND.
- Measured ox-CaMKII levels as a biomarker.
- Investigated the effects of Ang II infusion, NADPH oxidase activation, and CaMKII inhibition on sinoatrial node (SAN) cells.
- Employed a computational model of the SAN to simulate cell loss and impulse propagation.
Main Results:
- Oxidized calmodulin kinase II (ox-CaMKII) was identified as both a biomarker and a determinant of SND in patients and dogs.
- Angiotensin II infusion induced oxidative stress in SAN cells via NADPH oxidase, leading to ox-CaMKII accumulation, apoptosis, and SND in mice.
- Mice lacking NADPH oxidase or with CaMKII inhibition exhibited resistance to SAN apoptosis and SND.
- Computational modeling indicated that a critical loss of SAN cells precipitates SND.
Conclusions:
- Ox-CaMKII plays a crucial role in Ang II-induced SAN cell death and the development of SND.
- Targeted inhibition of CaMKII presents a potential therapeutic strategy for preventing SND in at-risk individuals.
