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.
View: Text | PDF
Research Article Cardiology Muscle biology

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

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

×

Figure 2

Global TREK-1 KO develops hypertrophy and maintains function after pressure overload.

Options: View larger image (or click on image) Download as PowerPoint
Global TREK-1 KO develops hypertrophy and maintains function after press...
(A) Serial echocardiographic measurements of average wall thicknesses (SWT + PWT) and (B) average change in wall thickness, (C) average FS ([EDD – ESD/EDD] × 100) and (D) average change in FS in TREK-1 KO and WT at baseline and up to 16 weeks after TAC. Error bars reflect SEM. Statistical comparisons between WT TAC and TREK-1–KO TAC data were made using 2-way repeated measures ANOVA. P values for the interaction between genotype and weeks after TAC are shown. Comparisons between genotypes at each time point were made using Bonferroni’s test for multiple comparisons. †P < 0.001; *P < 0.05 for WT TAC versus TREK-1–KO TAC at each time point. (E) Whole mount of hearts from WT and TREK-1–KO hearts both under sham and 16 weeks of TAC conditions. Representative wheat germ agglutinin (WGA) staining showing myocyte areas in WT and TREK-1 KO 16 weeks following sham or TAC. Scale bars: 50 μm. (F) Average myocyte cross-sectional area (CSA) in WT and TREK-1–KO cross-sectional area after 16 weeks of TAC. The average measured CSAs of 300–500 cardiomyocytes were used for each animal. Statistical comparisons were performed using 1-way ANOVA with Newman-Keuls test for multiple comparisons. *P < 0.05 versus WT sham.