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Augmentation of myocardial I f dysregulates calcium homeostasis and causes adverse cardiac remodeling

Augmentation of myocardial I f dysregulates calcium homeostasis and causes adverse cardiac remodeling

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, etc.

Nat Commun. 2019 Jul 23;10(1):3295.

PMID: 31337768

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP77108408	Troponin I from human heart		77108-40-8	Price

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