Cardiac expression and atrial fibrillation-associated remodeling of K2P2.1 (TREK-1) K+ channels in a porcine model

Schmidt, Constanze; Wiedmann, Felix; Tristram, Frank; Anand, Paras; Wenzel, Wolfgang; Lugenbiel, Patrick; Schweizer, Patrick; Katus, Hugo A.; Thomas, Dierk

doi:10.1016/j.lfs.2013.12.006

Cited by 42 publications

(34 citation statements)

References 39 publications

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“…Our findings suggest (1) that downregulation of TREK‐1–associated β IV ‐spectrin occurs in specific cardiac disease states to promote SAN dysfunction and (2) that loss of TREK‐1 function promotes abnormal SAN cell excitability and pacemaking defects. Interestingly, our new data align with recent studies that have shown dramatic reduction in TREK‐1 in the right atrium during persistent atrial fibrillation in the pig, suggesting a broader role for TREK‐1 dysfunction in atrial arrhythmogenesis 36. It is interesting to note that αMHC‐ Kcnk2 f/f animals show mild bradycardia at rest despite an increase in SAN cell membrane excitability (increased AP firing rate).…”

Section: Discussionsupporting

confidence: 89%

“…TREK‐1 expression has been reported throughout all regions of the heart3, 8, 10, 36; however, few data are available on relative levels of expressed protein in SAN, atrium, and ventricle. TREK‐1 protein expression was assessed in different mouse heart regions to determine whether differential expression could contribute to the predominant SAN phenotypes observed in αMHC‐ Kcnk2 f/f mice.…”

Section: Resultsmentioning

confidence: 99%

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Two‐Pore K ⁺ Channel TREK‐1 Regulates Sinoatrial Node Membrane Excitability

Unudurthi

Lei

et al. 2016

JAHA

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BackgroundTwo‐pore K+ channels have emerged as potential targets to selectively regulate cardiac cell membrane excitability; however, lack of specific inhibitors and relevant animal models has impeded the effort to understand the role of 2‐pore K+ channels in the heart and their potential as a therapeutic target. The objective of this study was to determine the role of mechanosensitive 2‐pore K+ channel family member TREK‐1 in control of cardiac excitability.Methods and ResultsCardiac‐specific TREK‐1–deficient mice (αMHC‐Kcnk f/f) were generated and found to have a prevalent sinoatrial phenotype characterized by bradycardia with frequent episodes of sinus pause following stress. Action potential measurements from isolated αMHC‐Kcnk2 f/f sinoatrial node cells demonstrated decreased background K+ current and abnormal sinoatrial cell membrane excitability. To identify novel pathways for regulating TREK‐1 activity and sinoatrial node excitability, mice expressing a truncated allele of the TREK‐1–associated cytoskeletal protein βIV‐spectrin (qv 4J mice) were analyzed and found to display defects in cell electrophysiology as well as loss of normal TREK‐1 membrane localization. Finally, the βIV‐spectrin/TREK‐1 complex was found to be downregulated in the right atrium from a canine model of sinoatrial node dysfunction and in human cardiac disease.ConclusionsThese findings identify a TREK‐1–dependent pathway essential for normal sinoatrial node cell excitability that serves as a potential target for selectively regulating sinoatrial node cell function.

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Section: Discussionsupporting

confidence: 89%

Section: Resultsmentioning

confidence: 99%

Two‐Pore K ⁺ Channel TREK‐1 Regulates Sinoatrial Node Membrane Excitability

Unudurthi

Lei

et al. 2016

JAHA

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“…Rapid electrical pacing of cultured cells in vitro or tissue in vivo is an established model of cardiac tachyarrhythmia that may induce electrophysiological remodeling similar to human findings [1,3,5,35,41,42]. In particular, tachypacing of HL-1 cells has been shown to cause action potential shortening [35].…”

Section: Tachypacing-associated Upregulation Of Kcnj5 Potassium Channmentioning

confidence: 99%

Inhibition of Histone Deacetylases Induces K+ Channel Remodeling and Action Potential Prolongation in HL-1 Atrial Cardiomyocytes

Lugenbiel

Govorov

Rahm

et al. 2018

Cell Physiol Biochem

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Background/Aims: Cardiac arrhythmias are triggered by environmental stimuli that may modulate expression of cardiac ion channels. Underlying epigenetic regulation of cardiac electrophysiology remains incompletely understood. Histone deacetylases (HDACs) control gene expression and cardiac integrity. We hypothesized that class I/II HDACs transcriptionally regulate ion channel expression and determine action potential duration (APD) in cardiac myocytes. Methods: Global class I/II HDAC inhibition was achieved by administration of trichostatin A (TSA). HDAC-mediated effects on K⁺ channel expression and electrophysiological function were evaluated in murine atrial cardiomyocytes (HL-1 cells) using real-time PCR, Western blot, and patch clamp analyses. Electrical tachypacing was employed to recapitulate arrhythmia-related effects on ion channel remodeling in the absence and presence of HDAC inhibition. Results: Global HDAC inhibition increased histone acetylation and prolonged APD₉₀ in atrial cardiomyocytes compared to untreated control cells. Transcript levels of voltage-gated or inwardly rectifying K⁺ channels Kcnq1, Kcnj3 and Kcnj5 were significantly reduced, whereas Kcnk2, Kcnj2 and Kcnd3 mRNAs were upregulated. Ion channel remodeling was similarly observed at protein level. Short-term tachypacing did not induce significant transcriptional K⁺ channel remodeling. Conclusion: The present findings link class I/II HDAC activity to regulation of ion channel expression and action potential duration in atrial cardiomyocytes. Clinical implications for HDAC-based antiarrhythmic therapy and cardiac safety of HDAC inhibitors require further investigation.

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“…131 Whole cell currents exhibiting the characteristics of recombinant TREK-1 (including sensitivity to volatile anaesthetics, arachidonic acid, pH, internal acidification, and stretch) have been observed in atrial and ventricular myocytes of several species including rat, mouse and pig. 137, 142 …”

Section: Cardiac Sac: Molecular Candidatesmentioning

confidence: 99%

“…136 In keeping with this, several well-established anti-arrhythmic drugs, including lidocaine, mexiletine, propafenone, carvedilol, dronedarone, and vernakalant, inhibit TREK-1. 142 …”

Section: Cardiac Sac: Molecular Candidatesmentioning

confidence: 99%

Cardiac Mechano-Gated Ion Channels and Arrhythmias

Peyronnet

Nerbonne

Kohl

2016

Circulation Research

179

167

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Mechanical forces will have been omnipresent since the origin of life, and living organisms have evolved mechanisms to sense, interpret and respond to mechanical stimuli. The cardiovascular system in general, and the heart in particular, are exposed to constantly changing mechanical signals, including stretch, compression, bending, and shear. The heart adjusts its performance to the mechanical environment, modifying electrical, mechanical, metabolic, and structural properties over a range of time scales. Many of the underlying regulatory processes are encoded intra-cardially, and are thus maintained even in heart transplant recipients. Although mechano-sensitivity of heart rhythm has been described in the medical literature for over a century, its molecular mechanisms are incompletely understood. Thanks to modern biophysical and molecular technologies, the roles of mechanical forces in cardiac biology are being explored in more detail, and detailed mechanisms of mechano-transduction have started to emerge. Mechano-gated ion channels are cardiac mechano-receptors. They give rise to mechano-electric feedback, thought to contribute to normal function, disease development, and, potentially, therapeutic interventions. In this review, we focus on acute mechanical effects on cardiac electrophysiology, explore molecular candidates underlying observed responses, and discuss their pharmaceutical regulation. From this, we identify open research questions and highlight emerging technologies that may help in addressing them. Cardiac electrophysiology is acutely affected by the heart’s mechanical environment. Mechano-electric feedback affects excitability, conduction, and electrical load, and remains an underestimated player in arrhythmogenesis. The utility of therapeutic interventions targeting acute mechano-electrical transduction is an open field worthy of further study.

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Cardiac expression and atrial fibrillation-associated remodeling of K2P2.1 (TREK-1) K+ channels in a porcine model

Cited by 42 publications

References 39 publications

Two‐Pore K ⁺ Channel TREK‐1 Regulates Sinoatrial Node Membrane Excitability

Two‐Pore K ⁺ Channel TREK‐1 Regulates Sinoatrial Node Membrane Excitability

Inhibition of Histone Deacetylases Induces K+ Channel Remodeling and Action Potential Prolongation in HL-1 Atrial Cardiomyocytes

Cardiac Mechano-Gated Ion Channels and Arrhythmias

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Cardiac expression and atrial fibrillation-associated remodeling of K2P2.1 (TREK-1) K+ channels in a porcine model

Cited by 42 publications

References 39 publications

Two‐Pore K + Channel TREK‐1 Regulates Sinoatrial Node Membrane Excitability

Two‐Pore K + Channel TREK‐1 Regulates Sinoatrial Node Membrane Excitability

Inhibition of Histone Deacetylases Induces K+ Channel Remodeling and Action Potential Prolongation in HL-1 Atrial Cardiomyocytes

Cardiac Mechano-Gated Ion Channels and Arrhythmias

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Two‐Pore K ⁺ Channel TREK‐1 Regulates Sinoatrial Node Membrane Excitability

Two‐Pore K ⁺ Channel TREK‐1 Regulates Sinoatrial Node Membrane Excitability