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

Beitrag in einer Fachzeitschrift
(Originalarbeit)


Details zur Publikation

Autorinnen und Autoren: 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
Zeitschrift: Molecular therapy : the journal of the American Society of Gene Therapy
Jahr der Veröffentlichung: 2015
Band: 23
Heftnummer: 8
Seitenbereich: 1320-30
ISSN: 1525-0024
Sprache: Englisch


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.



FAU-Autorinnen und Autoren / FAU-Herausgeberinnen und Herausgeber

Friedrich, Oliver Prof. Dr. Dr.
Lehrstuhl für Medizinische Biotechnologie


Einrichtungen weiterer Autorinnen und Autoren

Georg-August-Universität Göttingen
Ruprecht-Karls-Universität Heidelberg
Temple University
Thomas Jefferson University
Universitätsklinikum Heidelberg


Zitierweisen

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 : the journal of the American Society of Gene 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 : the journal of the American Society of Gene Therapy 23.8 (2015): 1320-30.

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Zuletzt aktualisiert 2018-10-08 um 23:16

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