The role of connexin40 in developing atrial conduction

Abstract

a b s t r a c tConnexin40 (Cx40) is the main connexin expressed in the murine atria and ventricular conduction system. We assess here the developmental role of Cx40 in atrial conduction of the mouse. Cx40 deficiency significantly prolonged activation times in embryonic day 10.5, 12.5 and 14.5 atria during spontaneous activation; the severity decreased with increasing age. In a majority of Cx40 deficient mice the impulse originated from an ectopic focus in the right atrial appendage; in such a case the activation time was even longer due to prolonged activation. Cx40 has thus an important physiological role in the developing atria.

Arrhythmias in the developing heart

“…At the time of heartbeat initiation, the first pacemaking activity was located in the left side of the sinus venosus, but within a few hours migrated to the right side, where the definitive pacemaker is located. A similar situation was reported also in avian embryos; remnants of this initial left-sided activity were reported in a small proportion of normal avian hearts at later stages of development (Sedmera et al 2006); under normal conditions, no such leftsided activity was reported in a large series of embryonic mice (Leaf et al 2008, Ammirabile et al 2012, Benes et al 2014.…”

Novel approaches to study coronary vasculature development in mice

“…From existing literature (Sankova et al, 2012;Benes et al, 2014), it does not appear that heterozygotes harbor any cardiac malformations, including coronary artery defects, which is in concordance with our findings. The heterozygotes have GFP positivity in the coronary vasculature, similar to homozygotes, and therefore are completely suitable for coronary artery imaging.…”

“…Homozygous Cx40:GFP knock-in mice were first described in 2004 (Miquerol et al, 2004) and are functionally null mice that remain viable and fertile. In addition, there is a conduction phenotype that includes a right bundle branch block (van Rijen et al, 2001) and abnormal atrial conduction (Leaf et al, 2008;Benes et al, 2014). Mice homozygous for the Cx40 deletion present with hypertension (Wagner et al, 2007) and an increased incidence of congenital heart disease (Simon et al, 1998).…”

“…Connexin40 (Cx40) is a conserved cardiac gap junction protein that, in addition to its well characterized expression in atrial myocytes and parts of the conduction system, is also expressed in arterial endothelial cells (Miquerol et al, 2004;Benes et al, 2014). Therefore, transgenic mice in which the enhanced green fluorescent protein (GFP) marker is expressed, instead of the Cx40 gene, show coronary artery-specific GFP expression.…”

“…Mice homozygous for the Cx40 deletion present with hypertension (Wagner et al, 2007) and an increased incidence of congenital heart disease (Simon et al, 1998). In addition, there is a conduction phenotype that includes a right bundle branch block (van Rijen et al, 2001) and abnormal atrial conduction (Leaf et al, 2008;Benes et al, 2014). However, heterozygotes have normal hearts with GFP expression mimicking that of the endogenous Cx40 gene (Sankova et al, 2012).…”