Differential Wnt-mediated programming and arrhythmogenesis in right versus left ventricles

Abstract

Several inherited arrhythmias, including Brugada syndrome and arrhythmogenic cardiomyopathy, primarily affect the right ventricle and can lead to sudden cardiac death. Among many differences, right and left ventricular cardiomyocytes derive from distinct progenitors, prompting us to investigate how embryonic programming may contribute to chamber-specific conduction and arrhythmia susceptibility. Here, we show that developmental perturbation of Wnt signaling leads to chamber-specific transcriptional regulation of genes important in cardiac conduction that persists into adulthood. Transcriptional profiling of right versus left ventricles in mice deficient in Wnt transcriptional activity reveals global chamber differences, including genes regulating cardiac electrophysiology such as Gja1 and Scn5a. In addition, the transcriptional repressor Hey2, a gene associated with Brugada syndrome, is a direct target of Wnt signaling in the right ventricle only. These transcriptional changes lead to perturbed right ventricular cardiac conduction and cellular excitability. Ex vivo and in vivo stimulation of the right ventricle is sufficient to induce ventricular tachycardia in Wnt transcriptionally inactive hearts, while left ventricular stimulation has no effect. These data show that embryonic perturbation of Wnt signaling in cardiomyocytes leads to right ventricular arrhythmia susceptibility in the adult heart through chamber-specific regulation of genes regulating cellular electrophysiology.

Cardioprotective actions of relaxin

“…Studies have shown that canonical Wnt signaling can suppress [82,182] or increase [124] Nav1.5 expression, and appears to be chamber specific with gain or loss of Wnt signaling altering Nav1.5 or showing no change depending on the heart chamber studied. [217] While it is unclear what is causing these discrepancies, different cell types, rodent models, age or techniques to activate or inhibit Wnt signaling may begin to explain them. As described in section 1.4, various studies have shown that RLX can activate cAMP signaling in certain cell types, though it has not been determined if cAMP activation by RLX is necessary for Nav1.5 regulation.…”

A novel dual reporter embryonic stem cell line for toxicological assessment of teratogen-induced perturbation of anterior–posterior patterning of the heart

“…Ventricular upregulation of the SMyHC3 transgene during embryogenesis was shown to precede adult-onset pathological hypertrophy upon deletion of the transcription factor Irx4 in the murine model (Bruneau et al 2001). Perturbed Wnt signaling during development can also lead to chamber-specific arrhythmias in adulthood due to underlying defects in chamber-specific gene expression (Li et al 2018). These effects are overlooked by the existing EST, and cannot be feasibly routinely tested in vivo, as pups from pregnant mothers in embryonic toxicity studies would necessarily be brought to term and subjected to ECG and telemetry recordings.…”

Transcriptional and Epigenetic Regulation of Cardiac Electrophysiology

“…More recently, we demonstrate how embryonic programming via the Wnt signaling pathway also regulates electrophysiology in a chamber-specific manner [23, 24]. It has long been postulated that Hey2 is regulated by mechanisms in addition to Notch signaling within the ventricles.…”

“…It has long been postulated that Hey2 is regulated by mechanisms in addition to Notch signaling within the ventricles. We demonstrate for the first time that Hey2 is a direct Wnt target only in the RV and not the LV, which may have relevance to our understanding of RV-specific arrhythmias [23]. Using both Wnt gain and loss-of-function approaches, additional genes regulating cardiac electrophysiology, Gja1 (gap junction alpha-1, encodes connexin 43) and Scn5a (encodes Na v 1.5 protein), were shown to be differentially regulated.…”