期刊
PROGRESS IN BIOPHYSICS & MOLECULAR BIOLOGY
卷 130, 期 -, 页码 233-243出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.pbiomolbio.2017.05.004
关键词
Stretch-activated ion channels; Two-pore-domain potassium channels; TREK-1; Atrial fibrillation; Heart failure
资金
- University of Heidelberg, Faculty of Medicine (Rahel Goitein-Straus Scholarship)
- DZHK (German Center for Cardiovascular Research)
- German Cardiac Society
- Hengstberger Foundation (Klaus-Georg and Sigrid Hengstberger Scholarship)
- German Heart Foundation/German Foundation of Heart Research [F/41/15, F/08/14]
- Else Kroner-Fresenius-Stiftung [2014_A242]
- Joachim Siebenreicher Foundation
- Deutsche Forschungsgemeinschaft (German Research Foundation) [SFB1002]
- Ministry of Science, Research and the Arts Baden-Wuerttemberg (Sonderlinie Medizin)
- Otto-Hess-Scholarship of the German Cardiac Society
- Kaltenbach-Scholarship of the German Heart Foundation/German Foundation of Heart Research
- German Federal Ministry of Education and Research via the e:Bio RNA-CODE joint research project [FKZ 031A298]
- German Research Foundation [DFG VO 1568/3-1, IRTG1816 RP12]
- Else-Kroner-Fresenius Stiftung [EKFS 2016_A20]
- University of Heidelberg, Faculty of Medicine (Olympia-Morata Scholarship)
Two-pore-domain potassium (K-2P) channels modulate cellular excitability. The significance of stretch activated cardiac K-2P channels (K(2P)2.1, TREK-I, KCNK2; K(2P)4.1, TRAAK, KCNK4; K(2P)10.1, TREK-2, KCNIC10) in heart disease has not been elucidated in detail. The aim of this work was to assess expression and remodeling of mechanosensitive K-2P channels in atrial fibrillation (AF) and heart failure (HF) patients in comparison to murine models. Cardiac K-2P channel levels were quantified in atrial (A) and ventricular (V) tissue obtained from patients undergoing open heart surgery. In addition, control mice and mouse models of AF (cAMP-response element modulator (CREM)-Ib Delta C-X transgenic animals) or HF (cardiac dysfunction induced by transverse aortic constriction, TAC) were employed. Human and murine KCNK2 displayed highest mRNA abundance among mechanosensitive members of the K-2P channel family (V > A). Disease-associated K(2P)2.1 remodeling was studied in detail. In patients with impaired left ventricular function, atrial ICCNIC2 (K(2P)2.1) mRNA and protein expression was significantly reduced. In AF subjects, downregulation of atrial and ventricular KCNK2 (K(2P)2.1) mRNA and protein levels was observed. AF-associated suppression of atrial Kcnk2 (K(2P)2.1) mRNA and protein was recapitulated in CREM-transgenic mice. Ventricular Kcnk2 expression was not significantly altered in mouse models of disease. In conclusion, mechanosensitive K(2P)2.1 and K(2P)10.1 K+ channels are expressed throughout the heart. HF- and AF-associated downregulation of KCNIC2 (K(2P)2.1) mRNA and protein levels suggest a mechanistic contribution to cardiac arrhythmogenesis. (C) 2017 Elsevier Ltd. All rights reserved.
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