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  1. Article ; Online: Reply to

    Trine L. Toft-Bertelsen / Mads Gravers Jeppesen / Asante Landbrug / Amer Mujezinovic / Bo Hjorth Bentzen / Thomas Nitschke Kledal / Mette Marie Rosenkilde

    Communications Biology, Vol 5, Iss 1, Pp 1-

    How Many SARS-CoV-2 “Viroporins” Are Really Ion Channels?

    2022  Volume 3

    Keywords Biology (General) ; QH301-705.5
    Language English
    Publishing date 2022-08-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Investigating gene-microRNA networks in atrial fibrillation patients with mitral valve regurgitation.

    Joana Larupa Santos / Ismael Rodríguez / Morten S Olesen / Bo Hjorth Bentzen / Nicole Schmitt

    PLoS ONE, Vol 15, Iss 5, p e

    2020  Volume 0232719

    Abstract: BACKGROUND:Atrial fibrillation (AF) is predicted to affect around 17.9 million individuals in Europe by 2060. The disease is associated with severe electrical and structural remodelling of the heart, and increased the risk of stroke and heart failure. In ...

    Abstract BACKGROUND:Atrial fibrillation (AF) is predicted to affect around 17.9 million individuals in Europe by 2060. The disease is associated with severe electrical and structural remodelling of the heart, and increased the risk of stroke and heart failure. In order to improve treatment and find new drug targets, the field needs to better comprehend the exact molecular mechanisms in these remodelling processes. OBJECTIVES:This study aims to identify gene and miRNA networks involved in the remodelling of AF hearts in AF patients with mitral valve regurgitation (MVR). METHODS:Total RNA was extracted from right atrial biopsies from patients undergoing surgery for mitral valve replacement or repair with AF and without history of AF to test for differentially expressed genes and miRNAs using RNA-sequencing and miRNA microarray. In silico predictions were used to construct a mRNA-miRNA network including differentially expressed mRNAs and miRNAs. Gene and chromosome enrichment analysis were used to identify molecular pathways and high-density AF loci. RESULTS:We found 644 genes and 43 miRNAs differentially expressed in AF patients compared to controls. From these lists, we identified 905 pairs of putative miRNA-mRNA interactions, including 37 miRNAs and 295 genes. Of particular note, AF-associated miR-130b-3p, miR-338-5p and miR-208a-3p were differentially expressed in our AF tissue samples. These miRNAs are predicted regulators of several differentially expressed genes associated with cardiac conduction and fibrosis. We identified two high-density AF loci in chromosomes 14q11.2 and 6p21.3. CONCLUSIONS:AF in MVR patients is associated with down-regulation of ion channel genes and up-regulation of extracellular matrix genes. Other AF related genes are dysregulated and several are predicted to be targeted by miRNAs. Our novel miRNA-mRNA regulatory network provides new insights into the mechanisms of AF.
    Keywords Medicine ; R ; Science ; Q
    Subject code 610
    Language English
    Publishing date 2020-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Endocannabinoids enhance hKV7.1/KCNE1 channel function and shorten the cardiac action potential and QT intervalResearch in context

    Irene Hiniesto-Iñigo / Laura M. Castro-Gonzalez / Valentina Corradi / Mark A. Skarsfeldt / Samira Yazdi / Siri Lundholm / Johan Nikesjö / Sergei Yu Noskov / Bo Hjorth Bentzen / D. Peter Tieleman / Sara I. Liin

    EBioMedicine, Vol 89, Iss , Pp 104459- (2023)

    2023  

    Abstract: Summary: Background: Genotype-positive patients who suffer from the cardiac channelopathy Long QT Syndrome (LQTS) may display a spectrum of clinical phenotypes, with often unknown causes. Therefore, there is a need to identify factors influencing disease ...

    Abstract Summary: Background: Genotype-positive patients who suffer from the cardiac channelopathy Long QT Syndrome (LQTS) may display a spectrum of clinical phenotypes, with often unknown causes. Therefore, there is a need to identify factors influencing disease severity to move towards an individualized clinical management of LQTS. One possible factor influencing the disease phenotype is the endocannabinoid system, which has emerged as a modulator of cardiovascular function. In this study, we aim to elucidate whether endocannabinoids target the cardiac voltage-gated potassium channel KV7.1/KCNE1, which is the most frequently mutated ion channel in LQTS. Methods: We used two-electrode voltage clamp, molecular dynamics simulations and the E4031 drug-induced LQT2 model of ex-vivo guinea pig hearts. Findings: We found a set of endocannabinoids that facilitate channel activation, seen as a shifted voltage-dependence of channel opening and increased overall current amplitude and conductance. We propose that negatively charged endocannabinoids interact with known lipid binding sites at positively charged amino acids on the channel, providing structural insights into why only specific endocannabinoids modulate KV7.1/KCNE1. Using the endocannabinoid ARA-S as a prototype, we show that the effect is not dependent on the KCNE1 subunit or the phosphorylation state of the channel. In guinea pig hearts, ARA-S was found to reverse the E4031-prolonged action potential duration and QT interval. Interpretation: We consider the endocannabinoids as an interesting class of hKV7.1/KCNE1 channel modulators with putative protective effects in LQTS contexts. Funding: ERC (No. 850622), Canadian Institutes of Health Research, Canada Research Chairs and Compute Canada, Swedish National Infrastructure for Computing.
    Keywords Arrhythmia ; Electrophysiology ; KCNQ1 ; Kv7 ; Long QT Syndrome ; Molecular dynamics ; Medicine ; R ; Medicine (General) ; R5-920
    Subject code 572
    Language English
    Publishing date 2023-03-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Central and Peripheral GABAA Receptor Regulation of the Heart Rate Depends on the Conscious State of the Animal

    Bo Hjorth Bentzen / Morten Grunnet

    Advances in Pharmacological Sciences, Vol

    2011  Volume 2011

    Abstract: Intuitively one might expect that activation of GABAergic inhibitory neurons results in bradycardia. In conscious animals the opposite effect is however observed. GABAergic neurons in nucleus ambiguus hold the ability to control the activity of the ... ...

    Abstract Intuitively one might expect that activation of GABAergic inhibitory neurons results in bradycardia. In conscious animals the opposite effect is however observed. GABAergic neurons in nucleus ambiguus hold the ability to control the activity of the parasympathetic vagus nerve that innervates the heart. Upon GABA activation the vagus nerve will be inhibited leaving less parasympathetic impact on the heart. The picture is however blurred in the presence of anaesthesia where both the concentration and type of anaesthetics can result in different effects on the cardiovascular system. This paper reviews cardiovascular outcomes of GABA activation and includes own experiments on anaesthetized animals and isolated hearts. In conclusion, the impact of changes in GABAergic input is very difficult to predict in these settings, emphasizing the need for experiments performed in conscious animals when aiming at determining the cardiovascular effects of compounds acting on GABAergic neurons.
    Keywords Medicine (General) ; R5-920 ; Therapeutics. Pharmacology ; RM1-950
    Subject code 590
    Language English
    Publishing date 2011-01-01T00:00:00Z
    Publisher Hindawi Publishing Corporation
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Author Correction

    Trine Lisberg Toft-Bertelsen / Mads Gravers Jeppesen / Eva Tzortzini / Kai Xue / Karin Giller / Stefan Becker / Amer Mujezinovic / Bo Hjorth Bentzen / Loren B. Andreas / Antonios Kolocouris / Thomas Nitschke Kledal / Mette Marie Rosenkilde

    Communications Biology, Vol 4, Iss 1, Pp 1-

    Amantadine inhibits known and novel ion channels encoded by SARS-CoV-2 in vitro

    2021  Volume 2

    Keywords Biology (General) ; QH301-705.5
    Language English
    Publishing date 2021-12-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Amantadine has potential for the treatment of COVID-19 because it inhibits known and novel ion channels encoded by SARS-CoV-2

    Trine Lisberg Toft-Bertelsen / Mads Gravers Jeppesen / Eva Tzortzini / Kai Xue / Karin Giller / Stefan Becker / Amer Mujezinovic / Bo Hjorth Bentzen / Loren B. Andreas / Antonios Kolocouris / Thomas Nitschke Kledal / Mette Marie Rosenkilde

    Communications Biology, Vol 4, Iss 1, Pp 1-

    2021  Volume 10

    Abstract: Toft-Bertelsen et al. describe repurposing of anti-influenza drug amantadine and its derivatives for the treatment of SARS-CoV-2. They show that Amantadine, Emodin and Xanthene show significant blockage of ionchannels formed by SARS-CoV-2 which are ... ...

    Abstract Toft-Bertelsen et al. describe repurposing of anti-influenza drug amantadine and its derivatives for the treatment of SARS-CoV-2. They show that Amantadine, Emodin and Xanthene show significant blockage of ionchannels formed by SARS-CoV-2 which are crucial for its assembly and pathophysiology.
    Keywords Biology (General) ; QH301-705.5
    Language English
    Publishing date 2021-12-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: A Novel Loss-of-Function Variant in the Chloride Ion Channel Gene Clcn2 Associates with Atrial Fibrillation

    Thea Hyttel Hansen / Yannan Yan / Gustav Ahlberg / Oliver Bundgaard Vad / Lena Refsgaard / Joana Larupa dos Santos / Nancy Mutsaers / Jesper Hastrup Svendsen / Morten Salling Olesen / Bo Hjorth Bentzen / Nicole Schmitt

    Scientific Reports, Vol 10, Iss 1, Pp 1-

    2020  Volume 10

    Abstract: Abstract Atrial Fibrillation (AF) is the most common cardiac arrhythmia. Its pathogenesis is complex and poorly understood. Whole exome sequencing of Danish families with AF revealed a novel four nucleotide deletion c.1041_1044del in CLCN2 shared by ... ...

    Abstract Abstract Atrial Fibrillation (AF) is the most common cardiac arrhythmia. Its pathogenesis is complex and poorly understood. Whole exome sequencing of Danish families with AF revealed a novel four nucleotide deletion c.1041_1044del in CLCN2 shared by affected individuals. We aimed to investigate the role of genetic variation of CLCN2 encoding the inwardly rectifying chloride channel ClC-2 as a risk factor for the development of familiar AF. The effect of the CLCN2 variant was evaluated by electrophysiological recordings on transiently transfected cells. We used quantitative PCR to assess CLCN2 mRNA expression levels in human atrial and ventricular tissue samples. The nucleotide deletion CLCN2 c.1041_1044del results in a frame-shift and premature stop codon. The truncated ClC-2 p.V347fs channel does not conduct current. Co-expression with wild-type ClC-2, imitating the heterozygote state of the patients, resulted in a 50% reduction in macroscopic current, suggesting an inability of truncated ClC-2 protein to form channel complexes with wild type channel subunits. Quantitative PCR experiments using human heart tissue from healthy donors demonstrated that CLCN2 is expressed across all four heart chambers. Our genetic and functional data points to a possible link between loss of ClC-2 function and an increased risk of developing AF.
    Keywords Medicine ; R ; Science ; Q
    Subject code 572
    Language English
    Publishing date 2020-01-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; Online: Characterization of Atrial and Ventricular Structural Remodeling in a Porcine Model of Atrial Fibrillation Induced by Atrial Tachypacing

    Carlotta Citerni / Jeppe Kirchhoff / Lisbeth Høier Olsen / Stefan Michael Sattler / Fabio Gentilini / Monica Forni / Augusta Zannoni / Morten Grunnet / Nils Edvardsson / Bo Hjorth Bentzen / Jonas Goldin Diness

    Frontiers in Veterinary Science, Vol

    2020  Volume 7

    Abstract: Background: Atrial fibrillation (AF) is characterized by electrical and structural remodeling. Irregular and/or fast atrio-ventricular (AV) conduction during AF can result in AV dyssynchrony, tachymyopathy, pressure and volume overload with subsequent ... ...

    Abstract Background: Atrial fibrillation (AF) is characterized by electrical and structural remodeling. Irregular and/or fast atrio-ventricular (AV) conduction during AF can result in AV dyssynchrony, tachymyopathy, pressure and volume overload with subsequent dilatation, valve regurgitation, and ventricular dysfunction with progression to heart failure.Objective: To gain further insight into the myocardial pathophysiological changes induced by right atrial tachypacing (A-TP) in a large animal model.Methods: A total of 28 Landrace pigs were randomized as 14 into AF-induced A-TP group and 14 pigs to control group. AF pigs were tachypaced for 43 ± 4 days until in sustained AF. Functional remodeling was investigated by echocardiography (after cardioversion to sinus rhythm). Structural remodeling was quantified by histological preparations with picrosirius red and immunohistochemical stainings.Results: A-TP resulted in decreased left ventricular ejection fraction (LVEF) accompanied by increased end-diastolic and end-systolic left atrium (LA) volume and area. In addition, A-TP was associated with mitral valve (MV) regurgitation, diastolic dysfunction and increased atrial and ventricular fibrotic extracellular matrix (ECM).Conclusions: A-TP induced AF with concomitant LV systolic and diastolic dysfunction, increased LA volume and area, and atrial and ventricular fibrosis.
    Keywords left ventricular dysfunction ; atrial fibrillation ; pig model ; remodeling ; echocardiography ; Veterinary medicine ; SF600-1100
    Subject code 630
    Language English
    Publishing date 2020-04-01T00:00:00Z
    Publisher Frontiers Media S.A.
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article ; Online: Fatty acid analogue N-arachidonoyl taurine restores function of IKs channels with diverse long QT mutations

    Sara I Liin / Johan E Larsson / Rene Barro-Soria / Bo Hjorth Bentzen / H Peter Larsson

    eLife, Vol

    2016  Volume 5

    Abstract: About 300 loss-of-function mutations in the IKs channel have been identified in patients with Long QT syndrome and cardiac arrhythmia. How specific mutations cause arrhythmia is largely unknown and there are no approved IKs channel activators for ... ...

    Abstract About 300 loss-of-function mutations in the IKs channel have been identified in patients with Long QT syndrome and cardiac arrhythmia. How specific mutations cause arrhythmia is largely unknown and there are no approved IKs channel activators for treatment of these arrhythmias. We find that several Long QT syndrome-associated IKs channel mutations shift channel voltage dependence and accelerate channel closing. Voltage-clamp fluorometry experiments and kinetic modeling suggest that similar mutation-induced alterations in IKs channel currents may be caused by different molecular mechanisms. Finally, we find that the fatty acid analogue N-arachidonoyl taurine restores channel gating of many different mutant channels, even though the mutations are in different domains of the IKs channel and affect the channel by different molecular mechanisms. N-arachidonoyl taurine is therefore an interesting prototype compound that may inspire development of future IKs channel activators to treat Long QT syndrome caused by diverse IKs channel mutations.
    Keywords polyunsaturated fatty acid ; antiarrhythmic ; KCNQ1 ; KCNE1 ; Kv7.1 ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
    Subject code 003 ; 572
    Language English
    Publishing date 2016-09-01T00:00:00Z
    Publisher eLife Sciences Publications Ltd
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  10. Article ; Online: KCNMA1 encoded cardiac BK channels afford protection against ischemia-reperfusion injury.

    Ewa Soltysinska / Bo Hjorth Bentzen / Maria Barthmes / Helle Hattel / A Brianne Thrush / Mary-Ellen Harper / Klaus Qvortrup / Filip J Larsen / Tomas A Schiffer / Jose Losa-Reyna / Julia Straubinger / Angelina Kniess / Morten Bækgaard Thomsen / Andrea Brüggemann / Stefanie Fenske / Martin Biel / Peter Ruth / Christian Wahl-Schott / Robert Christopher Boushel /
    Søren-Peter Olesen / Robert Lukowski

    PLoS ONE, Vol 9, Iss 7, p e

    2014  Volume 103402

    Abstract: Mitochondrial potassium channels have been implicated in myocardial protection mediated through pre-/postconditioning. Compounds that open the Ca2+- and voltage-activated potassium channel of big-conductance (BK) have a pre-conditioning-like effect on ... ...

    Abstract Mitochondrial potassium channels have been implicated in myocardial protection mediated through pre-/postconditioning. Compounds that open the Ca2+- and voltage-activated potassium channel of big-conductance (BK) have a pre-conditioning-like effect on survival of cardiomyocytes after ischemia/reperfusion injury. Recently, mitochondrial BK channels (mitoBKs) in cardiomyocytes were implicated as infarct-limiting factors that derive directly from the KCNMA1 gene encoding for canonical BKs usually present at the plasma membrane of cells. However, some studies challenged these cardio-protective roles of mitoBKs. Herein, we present electrophysiological evidence for paxilline- and NS11021-sensitive BK-mediated currents of 190 pS conductance in mitoplasts from wild-type but not BK-/- cardiomyocytes. Transmission electron microscopy of BK-/- ventricular muscles fibres showed normal ultra-structures and matrix dimension, but oxidative phosphorylation capacities at normoxia and upon re-oxygenation after anoxia were significantly attenuated in BK-/- permeabilized cardiomyocytes. In the absence of BK, post-anoxic reactive oxygen species (ROS) production from cardiomyocyte mitochondria was elevated indicating that mitoBK fine-tune the oxidative state at hypoxia and re-oxygenation. Because ROS and the capacity of the myocardium for oxidative metabolism are important determinants of cellular survival, we tested BK-/- hearts for their response in an ex-vivo model of ischemia/reperfusion (I/R) injury. Infarct areas, coronary flow and heart rates were not different between wild-type and BK-/- hearts upon I/R injury in the absence of ischemic pre-conditioning (IP), but differed upon IP. While the area of infarction comprised 28±3% of the area at risk in wild-type, it was increased to 58±5% in BK-/- hearts suggesting that BK mediates the beneficial effects of IP. These findings suggest that cardiac BK channels are important for proper oxidative energy supply of cardiomyocytes at normoxia and upon re-oxygenation after prolonged ...
    Keywords Medicine ; R ; Science ; Q
    Subject code 610
    Language English
    Publishing date 2014-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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