title: S100A1 DNA-based Inotropic Therapy Protects Against Proarrhythmogenic Ryanodine Receptor 2 Dysfunction.
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.
authors.affiliation: Molecular and Translational Cardiology, Department of Internal Medicine III, Heidelberg University Hospital, Heidelberg, Germany. Electronic address: jr54@uw.edu.
authors.forename: Julia
authors.initials: J
authors.lastname: Ritterhoff
authors.affiliation: Molecular and Translational Cardiology, Department of Internal Medicine III, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Mirko
authors.initials: M
authors.lastname: Völkers
authors.affiliation: Molecular and Translational Cardiology, Department of Internal Medicine III, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Seitz
authors.affiliation: Molecular and Translational Cardiology, Department of Internal Medicine III, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Kristin
authors.initials: K
authors.lastname: Spaich
authors.affiliation: Center for Translational Medicine, Department of Pharmacology, School of Medicine, Temple University, Philadelphia, Pennsylvania, USA.
authors.forename: Erhe
authors.initials: E
authors.lastname: Gao
authors.affiliation: Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
authors.forename: Karsten
authors.initials: K
authors.lastname: Peppel
authors.affiliation: Molecular and Translational Cardiology, Department of Internal Medicine III, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Sven T
authors.initials: ST
authors.lastname: Pleger
authors.affiliation: Institute of Pharmacology, Heart Research Center Göttingen, Georg-August-University Göttingen, Göttingen, Germany; German Center for Cardiovascular Research (DZHK), partner site Göttingen, Göttingen, Germany.
authors.forename: Wolfram H
authors.initials: WH
authors.lastname: Zimmermann
authors.affiliation: Institute of Medical Biotechnology, University of Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Friedrich
authors.affiliation: Institute of Physiology and Pathophysiology, Medical Biophysics, University of Heidelberg, Heidelberg, Germany.
authors.forename: Rainer H A
authors.initials: RHA
authors.lastname: Fink
authors.affiliation: Center for Translational Medicine, Department of Pharmacology, School of Medicine, Temple University, Philadelphia, Pennsylvania, USA.
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Koch
authors.affiliation: Molecular and Translational Cardiology, Department of Internal Medicine III, Heidelberg University Hospital, Heidelberg, Germany; German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Heidelberg, Germany.
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.affiliation: Molecular and Translational Cardiology, Department of Internal Medicine III, Heidelberg University Hospital, Heidelberg, Germany; Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania, USA; German Centre for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Heidelberg, Germany; uniQure GmbH Germany, Heidelberg, Germany. Electronic address: patrick.most@med.uni-heidelberg.de.
authors.forename: Patrick
authors.initials: P
authors.lastname: Most
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002147:Calmodulin / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004562:Electrocardiography; D018014:Gene Transfer Techniques; D006333:Heart Failure / Q000235:genetics* / Q000517:prevention & control; D008297:Male; D051379:Mice; D008856:Microscopy, Fluorescence; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology; D010766:Phosphorylation; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics* / Q000378:metabolism; D009418:S100 Proteins / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D022021:Tacrolimus Binding Proteins / Q000378:metabolism; D023822:Tissue Engineering / Q000379:methods
chemical_list: D002135:Calcium-Binding Proteins; D002147:Calmodulin; D018076:DNA, Complementary; D019837:Ryanodine Receptor Calcium Release Channel; D009418:S100 Proteins; C110294:S100A1 protein; C503114:Sri protein, mouse; C000592748:ryanodine receptor 2. mouse; D022021:Tacrolimus Binding Proteins; C403484:tacrolimus binding protein 1B; D002118:Calcium