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Augmentation of myocardial If dysregulates calcium homeostasis and causes adverse cardiac remodeling

HCN channels underlie the depolarizing funny current (If) that contributes importantly to cardiac pacemaking. If is upregulated in failing and infarcted hearts, but its implication in disease mechanisms remained unresolved. We generated transgenic mice (HCN4tg/wt) to assess functional consequences o...

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Main Authors: Yampolsky, Pessah (Author) , Koenen, Michael (Author) , Mosqueira, Matias (Author) , Geschwill, Pascal (Author) , Nauck, Sebastian (Author) , Witzenberger, Monika (Author) , Seyler, Claudia (Author) , Fink, Thomas (Author) , Kruska, Mathieu (Author) , Bruehl, Claus (Author) , Schwoerer, Alexander Peter (Author) , Ehmke, Heimo (Author) , Fink, Rainer (Author) , Draguhn, Andreas (Author) , Thomas, Dierk (Author) , Katus, Hugo (Author) , Schweizer, Patrick Alexander (Author)
Format: Article (Journal)
Language:English
Published: 23 July 2019
In: Nature Communications
Year: 2019, Volume: 10, Pages: 1-16
ISSN:2041-1723
DOI:10.1038/s41467-019-11261-2
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s41467-019-11261-2
Verlag, kostenfrei, Volltext: https://www.nature.com/articles/s41467-019-11261-2
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Author Notes:Pessah Yampolsky, Michael Koenen, Matias Mosqueira, Pascal Geschwill, Sebastian Nauck, Monika Witzenberger, Claudia Seyler, Thomas Fink, Mathieu Kruska, Claus Bruehl, Alexander P. Schwoerer, Heimo Ehmke, Rainer H. A. Fink, Andreas Draguhn, Dierk Thomas, Hugo A. Katus & Patrick A. Schweizer
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Summary:HCN channels underlie the depolarizing funny current (If) that contributes importantly to cardiac pacemaking. If is upregulated in failing and infarcted hearts, but its implication in disease mechanisms remained unresolved. We generated transgenic mice (HCN4tg/wt) to assess functional consequences of HCN4 overexpression-mediated If increase in cardiomyocytes to levels observed in human heart failure. HCN4tg/wt animals exhibit a dilated cardiomyopathy phenotype with increased cellular arrhythmogenicity but unchanged heart rate and conduction parameters. If augmentation induces a diastolic Na+ influx shifting the Na+/Ca2+ exchanger equilibrium towards ‘reverse mode’ leading to increased [Ca2+]i. Changed Ca2+ homeostasis results in significantly higher systolic [Ca2+]i transients and stimulates apoptosis. Pharmacological inhibition of If prevents the rise of [Ca2+]i and protects from ventricular remodeling. Here we report that augmented myocardial If alters intracellular Ca2+ homeostasis leading to structural cardiac changes and increased arrhythmogenicity. Inhibition of myocardial If per se may constitute a therapeutic mechanism to prevent cardiomyopathy.
Item Description:Gesehen am 17.12.2024
Im Titel ist "f" bei "If" tiefgestellt
Physical Description:Online Resource
ISSN:2041-1723
DOI:10.1038/s41467-019-11261-2

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