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S100A1 DNA-based Inotropic Therapy Protects Against Proarrhythmogenic Ryanodine Receptor 2 Dysfunction.

Ritterhoff J, Völkers M, Seitz A, Spaich K, Gao E, Peppel K, Pleger S, Zimmermann W, Friedrich O, Fink R, Koch W, Katus H, Most P (2015)

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Publication Language: English

Publication Status: Published

Publication Type: Journal article, Original article

Publication year: 2015

Journal

Book Volume: 23

Pages Range: 1320-30

Journal Issue: 8

URI: http://www.nature.com/mt/journal/v23/n8/full/mt201593a.html

DOI: 10.1038/mt.2015.93

Abstract

Restoring expression levels of the EF-hand calcium (Ca(2+)) sensor protein S100A1 has emerged as a key factor in reconstituting normal Ca(2+) handling in failing myocardium. Improved sarcoplasmic reticulum (SR) function with enhanced Ca(2+) resequestration appears critical for S100A1's cyclic adenosine monophosphate-independent inotropic effects but raises concerns about potential diastolic SR Ca(2+) leakage that might trigger fatal arrhythmias. This study shows for the first time a diminished interaction between S100A1 and ryanodine receptors (RyR2s) in experimental HF. Restoring this link in failing cardiomyocytes, engineered heart tissue and mouse hearts, respectively, by means of adenoviral and adeno-associated viral S100A1 cDNA delivery normalizes diastolic RyR2 function and protects against Ca(2+)- and β-adrenergic receptor-triggered proarrhythmogenic SR Ca(2+) leakage in vitro and in vivo. S100A1 inhibits diastolic SR Ca(2+) leakage despite aberrant RyR2 phosphorylation via protein kinase A and calmodulin-dependent kinase II and stoichiometry with accessory modulators such as calmodulin, FKBP12.6 or sorcin. Our findings demonstrate that S100A1 is a regulator of diastolic RyR2 activity and beneficially modulates diastolic RyR2 dysfunction. S100A1 interaction with the RyR2 is sufficient to protect against basal and catecholamine-triggered arrhythmic SR Ca(2+) leak in HF, combining antiarrhythmic potency with chronic inotropic actions.

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How to cite

APA:

Ritterhoff, J., Völkers, M., Seitz, A., Spaich, K., Gao, E., Peppel, K.,... Most, P. (2015). S100A1 DNA-based Inotropic Therapy Protects Against Proarrhythmogenic Ryanodine Receptor 2 Dysfunction. Molecular Therapy, 23(8), 1320-30. https://dx.doi.org/10.1038/mt.2015.93

MLA:

Ritterhoff, Julia, et al. "S100A1 DNA-based Inotropic Therapy Protects Against Proarrhythmogenic Ryanodine Receptor 2 Dysfunction." Molecular Therapy 23.8 (2015): 1320-30.

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