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

Publication ,  Journal Article
Abraham, DM; Lee, TE; Watson, LJ; Mao, L; Chandok, G; Wang, H-G; Frangakis, S; Pitt, GS; Shah, SH; Wolf, MJ; Rockman, HA
Published in: J Clin Invest
November 1, 2018

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.

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Published In

J Clin Invest

DOI

EISSN

1558-8238

Publication Date

November 1, 2018

Volume

128

Issue

11

Start / End Page

4843 / 4855

Location

United States

Related Subject Headings

  • Protein Domains
  • Potassium Channels, Tandem Pore Domain
  • Myocytes, Cardiac
  • Myocardium
  • Mice, Knockout
  • Mice
  • Immunology
  • Humans
  • Fibrosis
  • Fibroblasts
 

Citation

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Abraham, D. M., Lee, T. E., Watson, L. J., Mao, L., Chandok, G., Wang, H.-G., … Rockman, H. A. (2018). The two-pore domain potassium channel TREK-1 mediates cardiac fibrosis and diastolic dysfunction. J Clin Invest, 128(11), 4843–4855. https://doi.org/10.1172/JCI95945
Abraham, Dennis M., Teresa E. Lee, Lewis J. Watson, Lan Mao, Gurangad Chandok, Hong-Gang Wang, Stephan Frangakis, et al. “The two-pore domain potassium channel TREK-1 mediates cardiac fibrosis and diastolic dysfunction.J Clin Invest 128, no. 11 (November 1, 2018): 4843–55. https://doi.org/10.1172/JCI95945.
Abraham DM, Lee TE, Watson LJ, Mao L, Chandok G, Wang H-G, et al. The two-pore domain potassium channel TREK-1 mediates cardiac fibrosis and diastolic dysfunction. J Clin Invest. 2018 Nov 1;128(11):4843–55.
Abraham, Dennis M., et al. “The two-pore domain potassium channel TREK-1 mediates cardiac fibrosis and diastolic dysfunction.J Clin Invest, vol. 128, no. 11, Nov. 2018, pp. 4843–55. Pubmed, doi:10.1172/JCI95945.
Abraham DM, Lee TE, Watson LJ, Mao L, Chandok G, Wang H-G, Frangakis S, Pitt GS, Shah SH, Wolf MJ, Rockman HA. The two-pore domain potassium channel TREK-1 mediates cardiac fibrosis and diastolic dysfunction. J Clin Invest. 2018 Nov 1;128(11):4843–4855.

Published In

J Clin Invest

DOI

EISSN

1558-8238

Publication Date

November 1, 2018

Volume

128

Issue

11

Start / End Page

4843 / 4855

Location

United States

Related Subject Headings

  • Protein Domains
  • Potassium Channels, Tandem Pore Domain
  • Myocytes, Cardiac
  • Myocardium
  • Mice, Knockout
  • Mice
  • Immunology
  • Humans
  • Fibrosis
  • Fibroblasts