Transcription factor ETV1 is essential for rapid conduction in the heart
Akshay Shekhar, … , Glenn I. Fishman, David S. Park
Akshay Shekhar, … , Glenn I. Fishman, David S. Park
Published October 24, 2016
Citation Information: J Clin Invest. 2016;126(12):4444-4459. https://doi.org/10.1172/JCI87968.
View: Text | PDF
Research Article Cardiology Development

Transcription factor ETV1 is essential for rapid conduction in the heart

Abstract

Rapid impulse propagation in the heart is a defining property of pectinated atrial myocardium (PAM) and the ventricular conduction system (VCS) and is essential for maintaining normal cardiac rhythm and optimal cardiac output. Conduction defects in these tissues produce a disproportionate burden of arrhythmic disease and are major predictors of mortality in heart failure patients. Despite the clinical importance, little is known about the gene regulatory network that dictates the fast conduction phenotype. Here, we have used signal transduction and transcriptional profiling screens to identify a genetic pathway that converges on the NRG1-responsive transcription factor ETV1 as a critical regulator of fast conduction physiology for PAM and VCS cardiomyocytes. Etv1 was highly expressed in murine PAM and VCS cardiomyocytes, where it regulates expression of Nkx2-5, Gja5, and Scn5a, key cardiac genes required for rapid conduction. Mice deficient in Etv1 exhibited marked cardiac conduction defects coupled with developmental abnormalities of the VCS. Loss of Etv1 resulted in a complete disruption of the normal sodium current heterogeneity that exists between atrial, VCS, and ventricular myocytes. Lastly, a phenome-wide association study identified a link between ETV1 and bundle branch block and heart block in humans. Together, these results identify ETV1 as a critical factor in determining fast conduction physiology in the heart.

Authors

Akshay Shekhar, Xianming Lin, Fang-Yu Liu, Jie Zhang, Huan Mo, Lisa Bastarache, Joshua C. Denny, Nancy J. Cox, Mario Delmar, Dan M. Roden, Glenn I. Fishman, David S. Park

×

Figure 3

ETV1 expression is enriched in fast conduction tissues of embryonic and adult mammalian hearts.

Options: View larger image (or click on image) Download as PowerPoint
ETV1 expression is enriched in fast conduction tissues of embryonic and ...
(A) Whole-mount X-gal staining of Etv1nlz/+ murine hearts demonstrated Etv1 expression in regions of fast conduction (atrial myocytes, His-Purkinje network) within developing and mature hearts (E12.5, E16.5, P1, P21, P70). (B) Low-magnification views of lacZ expression within Etv1nlz/+ Cntn2EGFP/+ P21 hearts revealed identical expression of Cntn2-EGFP and Etv1-nlz in the left and right VCS. (C) Higher magnification of the Purkinje cell network showed overlapping expression of Cntn2-EGFP and Etv1-nlz within all VCS cells (bottom panels). Etv1-nlz expression was significantly lower in slowly conducting CNTN2-EGFP+ SA nodal (top panels) and AV nodal (middle panels) cells. Red arrows identify CNTN2-EGFP+ nodal regions. (D) Immunofluorescence staining for ETV1 in Cntn2EGFP/+ murine heart sections. ETV1 protein is expressed in Cx40-positive atrial myocytes and colocalizes with CNTN2-EGFP+ VCS cells with robust nuclear expression (white arrows). (E and F) Cardiac ETV1 expression pattern was conserved in pigs and humans. In Yucatan miniature pig (2 years old), ETV1 colocalizes with Cx40 in atrial myocytes and VCS cells (E), and in human fetal heart (16 weeks), ETV1 colocalizes with Cx40 in the atria and CNTN2 in Purkinje cells (F). SA, sinoatrial; AV, atrioventricular; PAM, pectinated atrial myocardium; His, bundle of His; PC, Purkinje cells. Scale bars: 100 μm (E12.5, E16.5, P1), 1 mm (P21, P70) (A); 1 mm (B); 500 μm (C); 20 μm (D–F).