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.
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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

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Figure 4

ETV1 is regulated by NRG1 signaling and is sufficient to drive CCS-lacZ expression.

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ETV1 is regulated by NRG1 signaling and is sufficient to drive CCS-lacZ ...
(A) Representative E9.5 X-gal–stained Etv1nlz/+ hearts after in vitro culture with vehicle control or NRG1 for 24 hours (left panels). Quantitative RT-PCR for Etv1 in E9.5 hearts cultured with vehicle control or NRG1 for 12, 24, or 48 hours (n = 3, middle panel). Immunofluorescence staining for ETV1 in E9.5 hearts cultured with vehicle control or NRG1 for 24 hours (right panels). (B) E9.5 X-gal–stained CCS-lacZ hearts after in vitro culture with Ad-CMV or Ad-ETV1 for 48 hours. Quantification of CCS-lacZ expression, determined as a ratio of lacZ-positive area to the total heart area (n = 3). (C) P1 Etv1nlz/+ mice were treated with AG825 (1 mg/kg, i.p.) daily for 7 days. Representative examples of X-gal–stained P8 Etv1nlz/+ hearts showed significant reduction of Etv1-nlz reporter gene expression with AG825 treatment (n = 8). White boxed region in middle panels corresponds to the location of higher-magnification images in the right panels. (D) Representative surface ECG traces of P8 Etv1nlz/+ mice treated with vehicle control or AG825 for 7 days (n = 8). LV, left ventricle; RA, right atria; LA, left atria. Data represent mean ± SEM. *P < 0.05, 2-tailed Student’s t test. Scale bars: 50 μm (A and B); 100 μm (C).