Abstract
The ventricular conduction system (VCS) orchestrates the harmonious contraction in every heartbeat. Defects in the VCS are often associated with life-threatening arrhythmias and also promote adverse remodeling in heart disease. We have previously established that the Irx3 homeobox gene regulates rapid electrical propagation in the VCS by modulating the transcription of gap junction proteins Cx40 and Cx43. However, it is unknown whether other factors contribute to the conduction defects observed in Irx3 knockout (Irx3−/−) mice. In this study, we show that during the early postnatal period, Irx3−/− mice develop morphological defects in the VCS which are temporally dissociated from changes in gap junction expression. These morphological defects were accompanied with progressive changes in the cardiac electrocardiogram including right bundle branch block. Hypoplastic VCS was not associated with increased apoptosis of VCS cardiomyocytes but with a lack of recruitment and maturation of ventricular cardiomyocytes into the VCS. Computational analysis followed by functional verification revealed that Irx3 promotes VCS-enriched transcripts targeted by Nkx2.5 and/or Tbx5. Altogether, these results indicate that, in addition to ensuring the appropriate expression of gap junctional channels in the VCS, Irx3 is necessary for the postnatal maturation of the VCS, possibly via its interactions with Tbx5 and Nkx2.5.
Highlights
The ventricular conduction system (VCS) orchestrates the harmonious contraction in every heartbeat
We show that Irx3−/− mice exhibit progressive changes in electrocardiogram (ECG) recordings during the early postnatal period, which is accompanied by structural deterioration of the VCS, similar to the developmental changes observed in Nkx2.5+/− mice[4,12] and that these defects are temporally distinct from the effects of the loss of Irx[3] on gap junction expression
Given the fact that Irx[3] interacts with Nkx2.514 and that conduction defects in mice with Nkx2.5 haploinsufficiency are linked to developmental deterioration of the HisPurkinje structure[4,7,8,12], we considered the possibility that Irx[3] might regulate VCS morphology
Summary
The ventricular conduction system (VCS) orchestrates the harmonious contraction in every heartbeat. We have previously established that the Irx[3] homeobox gene regulates rapid electrical propagation in the VCS by modulating the transcription of gap junction proteins Cx40 and Cx43 It is unknown whether other factors contribute to the conduction defects observed in Irx[3] knockout (Irx3−/−) mice. Computational analysis followed by functional verification revealed that Irx[3] promotes VCS-enriched transcripts targeted by Nkx2.5 and/or Tbx[5] These results indicate that, in addition to ensuring the appropriate expression of gap junctional channels in the VCS, Irx[3] is necessary for the postnatal maturation of the VCS, possibly via its interactions with Tbx[5] and Nkx2.5. These results suggest that Irx[3] plays an essential role in the postnatal maturation of the VCS, possibly via its interactions with Tbx[5] and Nkx2.5
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