Cardiac adenoviral S100A1 gene delivery rescues failing myocardium

J Clin Invest. 2004 Dec;114(11):1550-63. doi: 10.1172/JCI21454.


Cardiac-restricted overexpression of the Ca2+-binding protein S100A1 has been shown to lead to increased myocardial contractile performance in vitro and in vivo. Since decreased cardiac expression of S100A1 is a characteristic of heart failure, we tested the hypothesis that S100A1 gene transfer could restore contractile function of failing myocardium. Adenoviral S100A1 gene delivery normalized S100A1 protein expression in a postinfarction rat heart failure model and reversed contractile dysfunction of failing myocardium in vivo and in vitro. S100A1 gene transfer to failing cardiomyocytes restored diminished intracellular Ca2+ transients and sarcoplasmic reticulum (SR) Ca2+ load mechanistically due to increased SR Ca2+ uptake and reduced SR Ca2+ leak. Moreover, S100A1 gene transfer decreased elevated intracellular Na+ concentrations to levels detected in nonfailing cardiomyocytes, reversed reactivated fetal gene expression, and restored energy supply in failing cardiomyocytes. Intracoronary adenovirus-mediated S100A1 gene delivery in vivo to the postinfarcted failing rat heart normalized myocardial contractile function and Ca2+ handling, which provided support in a physiological context for results found in myocytes. Thus, the present study demonstrates that restoration of S100A1 protein levels in failing myocardium by gene transfer may be a novel therapeutic strategy for the treatment of heart failure.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenoviridae / genetics*
  • Adenoviridae / metabolism
  • Animals
  • COS Cells
  • Calcium / metabolism
  • Calcium-Binding Proteins* / genetics
  • Calcium-Binding Proteins* / metabolism
  • Calcium-Transporting ATPases / metabolism
  • Cardiac Output, Low / therapy*
  • Chlorocebus aethiops
  • Female
  • Gene Expression Regulation, Developmental
  • Gene Transfer Techniques
  • Genetic Therapy / methods*
  • Genetic Vectors
  • Heart / anatomy & histology
  • Heart / physiology*
  • Hemodynamics
  • Humans
  • Male
  • Myocardial Contraction
  • Myocardial Infarction / pathology
  • Myocardial Infarction / therapy
  • Myocardium / cytology
  • Myocardium / metabolism*
  • Myocardium / pathology
  • Myocytes, Cardiac / cytology
  • Myocytes, Cardiac / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • S100 Proteins
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases


  • Calcium-Binding Proteins
  • S100 Proteins
  • S100A1 protein
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Calcium-Transporting ATPases
  • Calcium