Abstract 3411: GATA6 is Required for Normal Patterning and Function of the Proximal Cardiac Conduction System
Central conduction system (CCS) disorders cause significant morbidity and morality. While device-based therapy for CCS diseases is effective, they are associated with significant long-term and short-term risks. A paradigm is emerging that transcription factors involved with cardiac and CCS development are required for proper maintenance of CCS structure and function in postnatal life. GATA6 is a zinc-finger domain transcription factor involved with cardiac development and differentiation; therefore, we sought to determine if GATA6 may also be involved with regulating CCS function. We show here that GATA6 is expressed within the adult murine CCS. Ventricular-restricted deletion of functional GATA6 was achieved by crossing MCL2v-Cre knock-in mice with GATA6 floxed mice. Acetylcholine esterase staining reveals hypoplasia of the mature atrioventricular node and proximal His-bundle (4.29±2.2 x106 μm3 vs. 7.74±1.4 x106 μm3; n=5, p<0.05), in the absence of ventricular GATA6. However, H&E staining shows that ventricular morphology remains normal while echocardiographic evaluation demonstrates preserved ventricular function in GATA6 mutant mice. Myocardial deletion of GATA6 also results in prolonged atrioventricular node conduction assessed by surface ECG (PR-interval = 44.1±3.2 ms vs. 38.6±3.4 ms; n=12, p<0.05) and invasive electrophysiological testing (atriohisian interval = 34.7±4.0 ms vs. 28.0±2.5 ms; n=12, p<0.05). These defects are associated with down-regulation of the helix-loop-helix-containing transcriptional repressor Id2 within the confines of the proximal CCS. Our results suggest GATA6 is required for normal patterning and function of the proximal CCS, by regulating Id2 expression, and identifies GATA6 as a novel target for potentially treating CCS disorders.