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Cardiac adenoviral S100A1 gene delivery rescues failing myocardium
Patrick Most, … , Andrew Remppis, Walter J. Koch
Patrick Most, … , Andrew Remppis, Walter J. Koch
Published December 1, 2004
Citation Information: J Clin Invest. 2004;114(11):1550-1563. https://doi.org/10.1172/JCI21454.
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Article Cardiology

Cardiac adenoviral S100A1 gene delivery rescues failing myocardium

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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

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Figure 8

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S100A1 modulates RyR2 activity in biphasic manner. Control SR vesicles s...
S100A1 modulates RyR2 activity in biphasic manner. Control SR vesicles show a Ca2+-dependent increase of [3H]-RyR binding in the presence of 0.5 mM Mg2+ and 10 mM caffeine. Addition of 1 μM S100A1 protein decreased [3H]-RyR at 150 nM free Ca2+ concentrations, while greater than approximately 300 nM free Ca2+ S100A1 increased [3H]-RyR binding to the cardiac SR Ca2+-release channel. Data are presented as mean ± SEM and expressed as cpm. Experiments (n = 3) were carried out in triplicate. *P < 0.05 vs. control.

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