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

Yampolsky, P., Koenen, M., Mosqueira, M., Geschwill, P., Nauck, S., Witzenberger, M., et al. (2019). Augmentation of myocardial If dysregulates calcium homeostasis and causes adverse cardiac remodeling. Nature Communications, 10(1): 3295, pp. 1-16. doi:10.1038/s41467-019-11261-2.

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Item Permalink: https://hdl.handle.net/21.11116/0000-0004-59CA-5 Version Permalink: https://hdl.handle.net/21.11116/0000-0004-59CB-4
Genre: Journal Article

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 Creators:
Yampolsky, Pessah1, 2, Author           
Koenen, Michael1, 3, 4, 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 P., Author
Ehmke, Heimo, Author
Fink, Rainer H. A., Author
Draguhn, Andreas, Author
Thomas, Dierk, Author
Katus, Hugo A., Author
Schweizer, Patrick A., Author
Affiliations:
1Department of Molecular Neurobiology, Max Planck Institute for Medical Research, Max Planck Society, ou_1497704              
2Emeritus Group Biophysics, Max Planck Institute for Medical Research, Max Planck Society, ou_1497712              
3Department of Cell Physiology, Max Planck Institute for Medical Research, Max Planck Society, ou_1497701              
4Abteilung Zellphysiologie, MPI for biophysical chemistry, Max Planck Society, ou_578558              

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 Abstract: 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.

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Language(s): eng - English
 Dates: 2015-06-192019-06-282019-07-232019-07-23
 Publication Status: Issued
 Pages: 16
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1038/s41467-019-11261-2
URI: https://www.ncbi.nlm.nih.gov/pubmed/31337768
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Title: Nature Communications
  Abbreviation : Nat. Commun.
Source Genre: Journal
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Publ. Info: London : Nature Publishing Group
Pages: - Volume / Issue: 10 (1) Sequence Number: 3295 Start / End Page: 1 - 16 Identifier: ISSN: 2041-1723
CoNE: https://pure.mpg.de/cone/journals/resource/2041-1723