Constanze Schmidt1, Felix Wiedmann1, Frank Tristram2, Priya Anand2, Wolfgang Wenzel2, Patrick Lugenbiel1, Patrick A Schweizer1, Hugo A Katus1, Dierk Thomas3. 1. Department of Cardiology, Medical University Hospital, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany. 2. Institute of Nanotechnology, Karlsruhe Institute of Technology, P.O. Box 3640, D-76021 Karlsruhe, Germany. 3. Department of Cardiology, Medical University Hospital, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany. Electronic address: dierk.thomas@med.uni-heidelberg.de.
Abstract
AIMS: Effective management of atrial fibrillation (AF) often remains an unmet need. Cardiac two-pore-domain K(+) (K2P) channels are implicated in action potential regulation, and their inhibition has been proposed as a novel antiarrhythmic strategy. K2P2.1 (TREK-1) channels are expressed in the human heart. This study was designed to identify and functionally express porcine K2P2.1 channels. In addition, we sought to analyze cardiac expression and AF-associated K2P2.1 remodeling in a clinically relevant porcine AF model. MAIN METHODS: Three pK2P2.1 isoforms were identified and amplified. Currents were recorded using voltage clamp electrophysiology in the Xenopus oocyte expression system. K2P2.1 remodeling was studied by quantitative real time PCR and Western blot in domestic pigs during AF induced by atrial burst pacing. KEY FINDINGS: Human and porcine K2P2.1 proteins share 99% identity. Residues involved in phosphorylation or glycosylation are conserved. Porcine K2P2.1 channels carried outwardly rectifying K(+) currents similar to their human counterparts. In pigs, K2P2.1 was expressed ubiquitously in the heart with predominance in the atrial tissue. AF was associated with time-dependent reduction of K2P2.1 protein in the RA by 70% (7 days of AF) and 80% (21 days of AF) compared to control animals in sinus rhythm. K2P2.1 expression in the left atrium, AV node, and ventricles was not affected by AF. SIGNIFICANCE: Similarities between porcine and human K2P2.1 channels indicate that the pig may represent a valid model for mechanistic and preclinical studies. AF-related atrial K2P2.1 remodeling has potential implications for arrhythmia maintenance and antiarrhythmic therapy.
AIMS: Effective management of atrial fibrillation (AF) often remains an unmet need. Cardiac two-pore-domain K(+) (K2P) channels are implicated in action potential regulation, and their inhibition has been proposed as a novel antiarrhythmic strategy. K2P2.1 (TREK-1) channels are expressed in the human heart. This study was designed to identify and functionally express porcine K2P2.1 channels. In addition, we sought to analyze cardiac expression and AF-associated K2P2.1 remodeling in a clinically relevant porcine AF model. MAIN METHODS: Three pK2P2.1 isoforms were identified and amplified. Currents were recorded using voltage clamp electrophysiology in the Xenopus oocyte expression system. K2P2.1 remodeling was studied by quantitative real time PCR and Western blot in domestic pigs during AF induced by atrial burst pacing. KEY FINDINGS:Human and porcine K2P2.1 proteins share 99% identity. Residues involved in phosphorylation or glycosylation are conserved. Porcine K2P2.1 channels carried outwardly rectifying K(+) currents similar to their human counterparts. In pigs, K2P2.1 was expressed ubiquitously in the heart with predominance in the atrial tissue. AF was associated with time-dependent reduction of K2P2.1 protein in the RA by 70% (7 days of AF) and 80% (21 days of AF) compared to control animals in sinus rhythm. K2P2.1 expression in the left atrium, AV node, and ventricles was not affected by AF. SIGNIFICANCE: Similarities between porcine and humanK2P2.1 channels indicate that the pig may represent a valid model for mechanistic and preclinical studies. AF-related atrial K2P2.1 remodeling has potential implications for arrhythmia maintenance and antiarrhythmic therapy.
Authors: Erin Harleton; Alessandra Besana; Parag Chandra; Peter Danilo; Tove S Rosen; Michael R Rosen; Michael Argenziano; Richard B Robinson; Steven J Feinmark Journal: Am J Physiol Heart Circ Physiol Date: 2014-11-26 Impact factor: 4.733
Authors: J Kisselbach; C Seyler; P A Schweizer; R Gerstberger; R Becker; H A Katus; D Thomas Journal: Br J Pharmacol Date: 2014-08-28 Impact factor: 8.739
Authors: Patrick Lugenbiel; Fabian Wenz; Katharina Govorov; Patrick A Schweizer; Hugo A Katus; Dierk Thomas Journal: PLoS One Date: 2015-03-16 Impact factor: 3.240
Authors: Michael J Wallace; Mona El Refaey; Pietro Mesirca; Thomas J Hund; Matteo E Mangoni; Peter J Mohler Journal: Front Genet Date: 2021-04-01 Impact factor: 4.599
Authors: Sathya D Unudurthi; Xiangqiong Wu; Lan Qian; Foued Amari; Birce Onal; Ning Li; Michael A Makara; Sakima A Smith; Jedidiah Snyder; Vadim V Fedorov; Vincenzo Coppola; Mark E Anderson; Peter J Mohler; Thomas J Hund Journal: J Am Heart Assoc Date: 2016-04-20 Impact factor: 5.501