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 7

Etv1 KO hearts have reduced expression of fast conduction genes.

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Etv1 KO hearts have reduced expression of fast conduction genes. (A–C) ...
(A–C) NKX2-5 (A), Cx40 (B), and NaV1.5 (C) expression was evaluated by immunofluorescence in P18 Etv1 WT and KO atria and proximal VCS. VCS cells were identified by CNTN2 expression. Nuclei were stained with DAPI (blue). (D) Western blots of Etv1 WT, Het, and KO atrial tissue lysates detecting NKX2-5, Cx40, and NaV1.5. Vinculin was used as loading control. (E) Densitometry quantification of protein levels (normalized to vinculin), displayed relative to WT (n = 6). (F) Quantitative RT-PCR of Etv1 WT and KO FACS-purified ventricular, atrial, and Purkinje myocytes detecting fast conduction gene RNA levels (normalized to Gapdh). Relative transcript levels of Nkx2-5, Gja5, Scn5a, and Tbx5, displayed relative to WT (n = 4). (G) Quantitative RT-PCR of Nkx2-5, Gja5, Scn5a, and Tbx5 from E9.5 Etv1 WT and KO hearts in culture treated with vehicle control or NRG1 for 24 hours (n = 4). ND, not detected. Data represent mean ± SEM. *P < 0.05, 1-way ANOVA (E and G) or 2-tailed Student’s t test (F). Scale bars: 50 μm (A–C).