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Short-term pacing in the mouse alters cardiac expression of connexin43
Andrianos Kontogeorgis1, Riyaz A Kaba, Eunice Kang
1Leon H, Charney Division of Cardiology, Department of Medicine, New York University School of Medicine, New York, NY, USA. a.kontogeorgis@imperial.ac.uk
Insights
Short-term ventricular pacing in mice alters connexin43 gap junction expression and localization. These early changes in cardiac cells precede functional deficits, offering insights into arrhythmia prevention.
Area of Science:
- Cardiology
- Molecular Biology
- Biochemistry
Background:
- Cardiac insults affect connexin43 (Cx43) gap junction protein abundance and localization, potentially leading to arrhythmias.
- Chronic dyssynchronous cardiac activation models show Cx43 redistribution in cardiomyocytes.
- Ventricular pacing may induce short-term alterations in mouse heart Cx43 expression and localization.
Purpose of the Study:
- To investigate the hypothesis that short-term ventricular pacing induces changes in Cx43 expression and localization in the mouse heart.
Main Methods:
- Wild-type mice underwent subdiaphragmatic ventricular pacing for six hours at a rate 10-15% above their sinus rate.
- Hearts were analyzed for Cx43 mRNA and protein levels, localization, and ubiquitination.
- Cardiac function, refractoriness, and arrhythmia inducibility were assessed.
Main Results:
- Short-term pacing significantly reduced connexin43 mRNA abundance.
- A partial redistribution of Cx43 from the sarcolemma to a non-sarcolemmal fraction was observed.
- Accumulation of ubiquitinated Cx43 occurred without significant changes in total Cx43 protein levels or cardiac function.
Conclusions:
- Short-term pacing induces early changes in connexin43 gap junction expression, potentially involving decreased production and slowed degradation.
- This murine model aids in studying pacing-induced molecular changes.
- Findings may help develop strategies to prevent gap junction remodeling and associated arrhythmias.
Background:
Cardiac insults such as ischemia, infarction, hypertrophy and dilatation are often accompanied by altered abundance and/or localization of the connexin43 gap junction protein, which may predispose towards arrhythmic complications. Models of chronic dyssynchronous cardiac activation have also been shown to result in redistribution of connexin43 in cardiomyocytes. We hypothesized that alterations in connexin43 expression and localization in the mouse heart might be induced by ventricular pacing over a short period of time.
Results:
The subdiaphragmatic approach was used to pace a series of wild type mice for six hours before the hearts were removed for analysis. Mice were paced at 10-15% above their average anesthetized sinus rate and monitored to ensure 1:1 capture. Short-term pacing resulted in a significant reduction in connexin43 mRNA abundance, a partial redistribution of connexin43 from the sarcolemma to a non-sarcolemmal fraction, and accumulation of ubiquitinated connexin43 without a significant change in overall connexin43 protein levels. These early pacing-induced changes in connexin43 expression were not accompanied by decreased cardiac function, prolonged refractoriness or increased inducibility into sustained arrhythmias.
Conclusion:
Our data suggest that short-term pacing is associated with incipient changes in the expression of the connexin43 gap junction, possibly including decreased production and a slowed rate of degradation. This murine model may facilitate the study of early molecular changes induced by pacing and may ultimately assist in the development of strategies to prevent gap junction remodeling and the associated arrhythmic complications of cardiac disease.
