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

Mol Ther. 2015 Aug;23(8):1320-1330. doi: 10.1038/mt.2015.93. Epub 2015 May 25.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism
  • Calcium-Binding Proteins / metabolism
  • Calmodulin / metabolism
  • DNA, Complementary / metabolism
  • Electrocardiography
  • Gene Transfer Techniques
  • Heart Failure / genetics*
  • Heart Failure / prevention & control
  • Male
  • Mice
  • Microscopy, Fluorescence
  • Myocardium / metabolism
  • Myocytes, Cardiac / cytology
  • Phosphorylation
  • Protein Binding
  • Rats
  • Rats, Sprague-Dawley
  • Ryanodine Receptor Calcium Release Channel / genetics*
  • Ryanodine Receptor Calcium Release Channel / metabolism
  • S100 Proteins / metabolism*
  • Sarcoplasmic Reticulum / metabolism
  • Tacrolimus Binding Proteins / metabolism
  • Tissue Engineering / methods

Substances

  • Calcium-Binding Proteins
  • Calmodulin
  • DNA, Complementary
  • Ryanodine Receptor Calcium Release Channel
  • S100 Proteins
  • S100A1 protein
  • Sri protein, mouse
  • ryanodine receptor 2. mouse
  • Tacrolimus Binding Proteins
  • tacrolimus binding protein 1B
  • Calcium