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Usage Information

The two-pore domain potassium channel TREK-1 mediates cardiac fibrosis and diastolic dysfunction
Dennis M. Abraham, … , Matthew J. Wolf, Howard A. Rockman
Dennis M. Abraham, … , Matthew J. Wolf, Howard A. Rockman
Published August 28, 2018
Citation Information: J Clin Invest. 2018;128(11):4843-4855. https://doi.org/10.1172/JCI95945.
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Research Article Cardiology Muscle biology

The two-pore domain potassium channel TREK-1 mediates cardiac fibrosis and diastolic dysfunction

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Abstract

Cardiac two-pore domain potassium channels (K2P) exist in organisms from Drosophila to humans; however, their role in cardiac function is not known. We identified a K2P gene, CG8713 (sandman), in a Drosophila genetic screen and show that sandman is critical to cardiac function. Mice lacking an ortholog of sandman, TWIK-related potassium channel (TREK-1, also known Kcnk2), exhibit exaggerated pressure overload–induced concentric hypertrophy and alterations in fetal gene expression, yet retain preserved systolic and diastolic cardiac function. While cardiomyocyte-specific deletion of TREK-1 in response to in vivo pressure overload resulted in cardiac dysfunction, TREK-1 deletion in fibroblasts prevented deterioration in cardiac function. The absence of pressure overload–induced dysfunction in TREK-1–KO mice was associated with diminished cardiac fibrosis and reduced activation of JNK in cardiomyocytes and fibroblasts. These findings indicate a central role for cardiac fibroblast TREK-1 in the pathogenesis of pressure overload–induced cardiac dysfunction and serve as a conceptual basis for its inhibition as a potential therapy.

Authors

Dennis M. Abraham, Teresa E. Lee, Lewis J. Watson, Lan Mao, Gurangad Chandok, Hong-Gang Wang, Stephan Frangakis, Geoffrey S. Pitt, Svati H. Shah, Matthew J. Wolf, Howard A. Rockman

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