Short-term pacing in the mouse alters cardiac expression of connexin43

Abstract

BackgroundCardiac 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.ResultsThe 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.ConclusionOur 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.

Biomechanics of Cardiac Electromechanical Coupling and Mechanoelectric Feedback

“…Mechanical loading increases expression of gap junction proteins through hypertrophy processes, which can lead to an increase in conduction velocity [85,86]. Alterations in cardiac mechanics via electrical stimulation and heart failure have also been observed to promote gap junction remodeling, increasing susceptibility to arrhythmia [83,87,88].…”

Speckle-Tracking Echocardiography Elucidates the Effect of Pacing Site on Left Ventricular Synchronization in the Normal and Infarcted Rat Myocardium

“…In addition, in the pioneering study of Bilchick et al 2006 mice were implanted with a single pacing electrode on the RV free wall and were paced for seven days using an implanted miniature pacemaker. Using microarray analysis, this study demonstrated indications for molecular polarization as a result of prolonged RV pacing [13,15]. Thus, it appears that rodents may mimic important features that are seen in large mammals in regard to the mechanical effect of ventricular pacing.…”

“…LV synchrony using M-mode echocardiography, [13,15] our study is the first to utilize speckled tracking analysis under various pacing modes in order to view the full segmental pattern during RA, RV, LV and BIV pacing. The results show clear beneficial effects of LV and to a greater extend BIV pacing on LV synchrony compared to RV pacing.…”

“…While rat and mouse models are extensively used in research on HF [14], these animal models are largely missing in research on DHF and CRT, mainly due to technical difficulties in electrode implantation. Two independent studies using M-mode echocardiography have managed to demonstrate dyssynchrony between the septum and the LV lateral wall in the murine heart [13,15]. In addition, in the pioneering study of Bilchick et al 2006 mice were implanted with a single pacing electrode on the RV free wall and were paced for seven days using an implanted miniature pacemaker.…”

Functional role of gap junctions in early and delayed cardioprotection induced by nitric oxide donors and rapid cardiac pacing

“…For example, Kontogeorgis et al [86] showed that pacing of mice hearts for 6 hours reduced endocardial Cx43 level and the redistribution of gap junctions. Similarly, Matsushita et al [87] demonstrated that cardiac pacing for 3 hours caused dephosphorylation of Cx43 at the vicinity of the pacing site.…”