Cardiac adenoviral S100A1 gene delivery rescues failing myocardium.

Abstract

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.

• Authors: Patrick Most, Sven T Pleger, Mirko Völkers, Beatrix Heidt, Melanie Boerries, Dieter Weichenhan, Eva Löffler, Paul M L Janssen, Andrea D Eckhart, Jeffrey Martini, Matthew L Williams, Hugo A Katus, Andrew Remppis, Walter J Koch
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 114 Issue 11 Pg. 1550-63 (Dec 2004) ISSN: 0021-9738 [Print] United States
• PMID: 15578088 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

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

Topics

• Adenoviridae (genetics, metabolism)
• Animals
• COS Cells
• Calcium (metabolism)
• Calcium-Binding Proteins (genetics, 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, physiology)
• Hemodynamics
• Humans
• Male
• Myocardial Contraction
• Myocardial Infarction (pathology, therapy)
• Myocardium (cytology, metabolism, pathology)
• Myocytes, Cardiac (cytology, metabolism)
• Rats
• Rats, Sprague-Dawley
• S100 Proteins
• Sarcoplasmic Reticulum Calcium-Transporting ATPases