The two-pore domain potassium channel TREK-1 mediates cardiac fibrosis and diastolic dysfunction.
Journal Article (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 1, 2018
Published In
Volume / Issue
- 128 / 11
Start / End Page
- 4843 - 4855
PubMed ID
- 30153110
Pubmed Central ID
- PMC6205385
Electronic International Standard Serial Number (EISSN)
- 1558-8238
Digital Object Identifier (DOI)
- 10.1172/JCI95945
Language
- eng
Conference Location
- United States