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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Abraham, DM; Lee, TE; Watson, LJ; Mao, L; Chandok, G; Wang, H-G; Frangakis, S; Pitt, GS; Shah, SH; Wolf, MJ; Rockman, HA

Published Date

  • November 2018

Published In

Volume / Issue

  • 128 / 11

Start / End Page

  • 4843 - 4855

PubMed ID

  • 30153110

Pubmed Central ID

  • 30153110

Electronic International Standard Serial Number (EISSN)

  • 1558-8238

International Standard Serial Number (ISSN)

  • 0021-9738

Digital Object Identifier (DOI)

  • 10.1172/JCI95945

Language

  • eng