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

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Figure 3

Global TREK-1 KO develops hypertrophic molecular signatures after pressure overload.

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Global TREK-1 KO develops hypertrophic molecular signatures after pressu...
(A) Average β-MHC to α-MHC ratio and (B) skeletal muscle actin gene expression in LVs after 2 weeks of TAC. For gene expression studies in panels A and B, statistical comparisons with WT sham, which has a theoretical mean of 1, were made with a 1-sample, 2-tailed t test. *P < 0.05 versus WT sham. Comparisons among all other groups excluding WT sham were made using by Kruskal-Wallis test with Dunn’s multiple comparisons test. †P < 0.05 versus TREK-1 KO sham. (C) CaMKII activity, as measured by phosphorylated phospholamban at threonine 17. Densitometry quantification of the ratio of phosphorylated phospholamban to total phospholamban, normalized to WT sham condition. Full, uncut gels are shown in the supplemental material. (D) Calcineurin activity as measured by RCAN1 gene expression from cDNA obtained from WT and TREK-1–KO LVs after sham or TAC. For the phospholamban (shown in C) and calcineurin experiments (shown D), statistical comparisons with WT sham, which has a theoretical mean of 1, were made with a 1-sample, 2-tailed t test. *P < 0.05 versus WT sham. Comparisons among all other groups excluding WT sham were made using by Kruskal-Wallis test with Dunn’s multiple comparisons test. †P < 0.05 versus WT TAC.