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Atrial fibrillation and heart failure-associated remodeling of two-pore-domain potassium (K2P) channels in murine disease models: focus on TASK-1

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Abstract

Understanding molecular mechanisms involved in atrial tissue remodeling and arrhythmogenesis in atrial fibrillation (AF) is essential for developing specific therapeutic approaches. Two-pore-domain potassium (K2P) channels modulate cellular excitability, and TASK-1 (K2P3.1) currents were recently shown to alter atrial action potential duration in AF and heart failure (HF). Finding animal models of AF that closely resemble pathophysiological alterations in human is a challenging task. This study aimed to analyze murine cardiac expression patterns of K2P channels and to assess modulation of K2P channel expression in murine models of AF and HF. Expression of cardiac K2P channels was quantified by real-time qPCR and immunoblot in mouse models of AF [cAMP-response element modulator (CREM)-IbΔC-X transgenic animals] or HF (cardiac dysfunction induced by transverse aortic constriction, TAC). Cloned murine, human, and porcine TASK-1 channels were heterologously expressed in Xenopus laevis oocytes. Two-electrode voltage clamp experiments were used for functional characterization. In murine models, among members of the K2P channel family, TASK-1 expression displayed highest levels in both atrial and ventricular tissue samples. Furthermore, K2P2.1, K2P5.1, and K2P6.1 showed significant expression levels. In CREM-transgenic mice, atrial expression of TASK-1 was significantly reduced in comparison with wild-type animals. In a murine model of TAC-induced pressure overload, ventricular TASK-1 expression remained unchanged, while atrial TASK-1 levels were significantly downregulated. When heterologously expressed in Xenopus oocytes, currents of murine, porcine, and human TASK-1 displayed similar characteristics. TASK-1 channels display robust cardiac expression in mice. Murine, porcine, and human TASK-1 channels share functional similarities. Dysregulation of atrial TASK-1 expression in murine AF and HF models suggests a mechanistic contribution to arrhythmogenesis.

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Abbreviations

A:

Atrium

AF:

Atrial fibrillation

APD:

Action potential duration

AVN:

Atrioventricular node

CASQ:

Calsequestrin

CaV:

Voltage-gated calcium channel

CREM:

CAMP-response element modulator

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase

HF:

Heart failure

IPO8:

Importin 8

K2P :

Two-pore-domain potassium channel

Kcnip2:

Voltage-gated potassium channel interacting protein 2

Kir:

Potassium inward rectifier

KV :

Voltage-gated potassium channel

LA:

Left atrium

LAA:

Left atrial appendage

m:

Murine

M-mode:

Motion mode

NaV :

Voltage-gated sodium channel

RA:

Right atrium

RAA:

Right atrial appendage

RVOT:

Right ventricular outflow tract

RYR:

Ryanodine receptor

SAN:

Sinoatrial node

SR:

Sinus rhythm

SUR:

Sulfonylurea receptor

TAC:

Transverse aortic constriction

TALK:

TWIK-related alkaline pH-activated K+ channel

TASK:

TWIK-related acid-sensitive K+ channel

TG:

Transgene

THIK:

Tandem pore domain in a halothane-inhibited K+ channel

TRAAK:

TWIK-related arachidonic acid-stimulated K+ channel

TREK:

TWIK-related K+ channel

TRESK:

TWIK-related spinal cord K+ channel

TWIK:

Tandem of pore domains in a weak inward rectifying channel

V:

Ventricle

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Acknowledgements

The excellent technical support of Katrin Kupser, Kai Sona and Stefanie Triebel is gratefully acknowledged. This study was supported in part by research grants from the University of Heidelberg, Faculty of Medicine (Rahel Goitein-Straus Scholarship and Olympia-Morata Scholarship to C. S.), from the DZHK (German Center for Cardiovascular Research; Excellence Grant to C. S.), from the German Cardiac Society and the Hengstberger Foundation (Klaus-Georg and Sigrid Hengstberger Scholarship to D. T.), from the German Heart Foundation/German Foundation of Heart Research (F/41/15 to C. S., F/08/14 to D.T.), from the Else Kröner-Fresenius-Stiftung (2014_A242 to D. T. and EKFS 2016_A20 to N. V.), from the Joachim Siebenreicher Foundation (to D. T.), from the Deutsche Forschungsgemeinschaft (German Research Foundation; SCHM 3358/1-1 to C. S., TH 1120/7-1 to D. T., MU 1376/11-3 to F. U. M and VO 1568/3-1, IRTG1816 RP12, SFB1002 TPA13 to N. V.), and from the Ministry of Science, Research and the Arts Baden-Wuerttemberg (Sonderlinie Medizin to D. T.). F. W. was supported by the German Cardiac Society (Fellowship and Otto-Hess-Scholarship), and A. R. was supported by the Kaltenbach-Scholarship of the German Heart Foundation/German Foundation of Heart Research.

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Authors and Affiliations

  1. Department of Cardiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany

    Felix Wiedmann, Bruna Gomes, Antonius Ratte, Dierk Thomas, Hugo A. Katus & Constanze Schmidt

  2. DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg/Mannheim, University of Heidelberg, Heidelberg, Germany

    Felix Wiedmann, Dierk Thomas, Hugo A. Katus & Constanze Schmidt

  3. HCR, Heidelberg Center for Heart Rhythm Disorders, University of Heidelberg, Heidelberg, Germany

    Felix Wiedmann, Antonius Ratte, Dierk Thomas, Hugo A. Katus & Constanze Schmidt

  4. Institute for Pharmacology and Toxicology, University of Münster, Münster, Germany

    Jan S. Schulte, Edda Fehrmann, Beatrix Scholz & Frank Ulrich Müller

  5. Institute of Pharmacology and Toxicology, University Medical Center Göttingen, Georg-August University Göttingen, Göttingen, Germany

    Maria-Patapia Zafeiriou, Franziska Rathjens & Niels Voigt

  6. DZHK (German Center for Cardiovascular Research), Partner Site Göttingen, Göttingen, Germany

    Maria-Patapia Zafeiriou, Franziska Rathjens & Niels Voigt

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  1. Felix Wiedmann
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  2. Jan S. Schulte
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Correspondence to Constanze Schmidt.

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Animal experiments were carried out in accordance with the Guide for the Care and Use of Laboratory Animals as adopted and promulgated by the US National Institutes of Health (NIH publication No. 86-23, revised 1985) and with EU Directive 2010/63/EU, and the current version of the German Law on the Protection of Animals was followed. The manuscript does not contain clinical studies or patient data.

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Wiedmann, F., Schulte, J.S., Gomes, B. et al. Atrial fibrillation and heart failure-associated remodeling of two-pore-domain potassium (K2P) channels in murine disease models: focus on TASK-1. Basic Res Cardiol 113, 27 (2018). https://doi.org/10.1007/s00395-018-0687-9

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