1. The two-pore domain potassium channel TREK-1 mediates cardiac fibrosis and diastolic dysfunction
- Author
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Stephan Frangakis, Lan Mao, Svati H. Shah, Matthew J. Wolf, Lewis J. Watson, Hong-Gang Wang, Howard A. Rockman, Geoffrey S. Pitt, Gurangad S. Chandok, Teresa E. Lee, and Dennis M. Abraham
- Subjects
0301 basic medicine ,Cardiac function curve ,medicine.medical_specialty ,Cardiac fibrosis ,Diastole ,Concentric hypertrophy ,Cardiomegaly ,030204 cardiovascular system & hematology ,Mice ,03 medical and health sciences ,Potassium Channels, Tandem Pore Domain ,0302 clinical medicine ,Protein Domains ,Fibrosis ,Internal medicine ,medicine ,Animals ,Humans ,Myocytes, Cardiac ,Mice, Knockout ,Pressure overload ,business.industry ,Myocardium ,General Medicine ,Fibroblasts ,medicine.disease ,Potassium channel ,Drosophila melanogaster ,030104 developmental biology ,Endocrinology ,Heart failure ,cardiovascular system ,business ,Research Article - 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. more...
- Published
- 2018
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