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 5

Activated NRG1 signaling is restricted to regions of fast conduction and results in activation of ETV1.

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Activated NRG1 signaling is restricted to regions of fast conduction and...
(A) Immunofluorescence staining of NRG1, pErbB4, pErbB2, pERK1/2, ETV1, and Cx40 in E13.5 embryonic heart serial sections. (B and C) Immunofluorescence staining of NRG1 (B) and pErbB4 (C) in P21 atria and the His-Purkinje system. (D and E) Cultured neonatal rat atrial myocytes treated with vehicle control or NRG1 for 0, 1, or 3 hours were evaluated for ETV1 phosphorylation and nuclear accumulation. (D) ETV1 was immunoprecipitated from cell lysates followed by Western blot analysis to detect phosphoserine residues (p-Ser). Densitometry quantification of p-Ser levels (normalized to ETV1) presented relative to baseline (n = 4). (E) Nuclear accumulation of ETV1 with NRG1 treatment was detected using immunofluorescence staining. Percentage of ETV1 nuclear-positive area presented with respect to DAPI-positive area (dashed circles) (n = 20 cells). Nuclei were stained with DAPI; atrial myocytes were identified by α-actinin staining (blue, DAPI; red, ETV1; green, actinin). LA, left atria; LV, left ventricle. Data represent mean ± SEM. *P < 0.05, 2-tailed Student’s t test. Scale bars: 50 μm (A); 25 μm (B and C); 5 μm (E).