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

J Clin Invest. 2018 Nov 1;128(11):4843-4855. doi: 10.1172/JCI95945. Epub 2018 Oct 2.

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.

Keywords: Cardiology; Cardiovascular disease; Fibrosis; Heart failure; Muscle Biology.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cardiomegaly / genetics
  • Cardiomegaly / metabolism*
  • Cardiomegaly / pathology
  • Drosophila melanogaster
  • Fibroblasts / metabolism*
  • Fibroblasts / pathology
  • Fibrosis
  • Humans
  • Mice
  • Mice, Knockout
  • Myocardium / metabolism*
  • Myocardium / pathology
  • Myocytes, Cardiac / metabolism*
  • Myocytes, Cardiac / pathology
  • Potassium Channels, Tandem Pore Domain / genetics
  • Potassium Channels, Tandem Pore Domain / metabolism*
  • Protein Domains

Substances

  • Potassium Channels, Tandem Pore Domain
  • potassium channel protein TREK-1