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

The Journal of Clinical Investigation
Dennis M AbrahamHoward A Rockman

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.

References

Sep 25, 1991·Proceedings of the National Academy of Sciences of the United States of America·H A RockmanK R Chien
Jul 1, 1993·The Journal of Clinical Investigation·K P AndersonS V Karwandee
Aug 4, 1998·The EMBO Journal·A J PatelM Lazdunski
Sep 10, 1999·The Journal of Biological Chemistry·F MaingretE Honoré
Jun 3, 2000·The EMBO Journal·F MaingretE Honoré
Jul 25, 2000·Circulation·B H Lorell, B A Carabello
May 6, 2003·The Journal of Biological Chemistry·Delphine JavelaudAlain Mauviel
May 7, 2004·The New England Journal of Medicine·Michael R ZileWilliam H Gaasch
Jul 2, 2005·Progress in Cardiovascular Diseases·Jean G F Bronzwaer, Walter J Paulus
Jul 12, 2005·The Journal of Biological Chemistry·Janet MurbartiánDouglas A Bayliss
Oct 27, 2005·Cardiovascular Research· Xian Tao LiJürgen Daut
Jan 25, 2006·Proceedings of the National Academy of Sciences of the United States of America·Matthew J WolfHoward A Rockman
Apr 4, 2006·Biochemical and Biophysical Research Communications·Hideo TachibanaHoward A Rockman
Jul 21, 2006·The New England Journal of Medicine·Theophilus E OwanMargaret M Redfield
May 23, 2007·Heart Failure Reviews·Mitra RajabiHeinrich Taegtmeyer
May 2, 2008·European Biophysics Journal : EBJ·Alison Gurney, Boris Manoury
Nov 13, 2008·The New England Journal of Medicine·Barry M MassieUNKNOWN I-PRESERVE Investigators
Jul 28, 2009·American Journal of Physiology. Heart and Circulatory Physiology·ByungSu YooHoward A Rockman
Jan 9, 2010·Circulation Research·Rahul Kakkar, Richard T Lee
Apr 2, 2010·American Journal of Physiology. Regulatory, Integrative and Comparative Physiology·Khodadad NamiranianRobert M Bryan
Jun 10, 2010·Science Signaling·Kriti RakeshHoward A Rockman
Oct 16, 2010·Cardiovascular Therapeutics·Lakshman Goonetilleke, John Quayle
Mar 25, 2011·Genesis : the Journal of Genetics and Development·Asha AcharyaMichelle D Tallquist
Jan 10, 2012·Methods in Molecular Biology·Honey B GoldenDavid E Dostal
Feb 23, 2012·The Journal of Clinical Investigation·Alexander FroeseThomas Brand
Oct 2, 2012·Developmental Cell·Jennifer DavisJeffery D Molkentin
Jan 3, 2013·The Journal of Clinical Investigation·Andrew R Marks
Mar 7, 2013·JAMA : the Journal of the American Medical Association·Ankur GulatiSanjay K Prasad
Dec 18, 2013·The Journal of Investigative Dermatology·Marion SchumacherBettina Hartenstein
Jan 22, 2014·Cardiovascular Research·Thomas J HundPeter J Mohler

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Citations

Sep 13, 2019·Pflügers Archiv : European journal of physiology·Samuel KamathamSalvatore Mancarella
Jul 15, 2020·Circulation Research·Michael T DavidsonDeborah M Muoio
Oct 23, 2019·International Journal of Molecular Sciences·Felix WiedmannConstanze Schmidt
Apr 10, 2019·Neural Regeneration Research·J Antonio Lamas, Diego Fernández-Fernández
Jan 25, 2020·American Journal of Physiology. Heart and Circulatory Physiology·Wei DuanDennis M Abraham
Aug 29, 2020·Cells·Margarida LorigoElisa Cairrao
Nov 3, 2020·Cardiovascular Research·Nikolaos G Frangogiannis
Jun 20, 2020·Progress in Biophysics and Molecular Biology·Felix WiedmannConstanze Schmidt
Jul 18, 2019·JACC. Basic to Translational Science·Claudio Humeres, Nikolaos G Frangogiannis
Sep 29, 2020·Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology·Pierluigi MarianiLuigi Laino
Apr 13, 2021·Frontiers in Pharmacology·Verena HofschröerAlbrecht Schwab
Feb 16, 2020·Cell Chemical Biology·Lianne PopeDaniel L Minor
Apr 23, 2021·Journal of Molecular Biology·Andrew M NataleDaniel L Minor
Jun 26, 2021·The Journal of Membrane Biology·Sanjiv SinghV Ravichandiran
Jul 3, 2021·International Journal of Molecular Sciences·Salvador Herrera-PérezJosé Antonio Lamas
Aug 28, 2021·International Journal of Molecular Sciences·Miklós LengyelGábor Czirják

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Methods Mentioned

BETA
transgenic
reverse transcription PCR
biopsy
SMA
protein assay
PCR
Chip

Software Mentioned

GraphPad Prism
Bio
ImageJ
PVAN
VisualSonics
GraphPad
MetaMorph
Rad Fluor - S MultiImager

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