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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 1

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Postinfarct heart failure model. (A) Representative TTC-stained cross-se...
Postinfarct heart failure model. (A) Representative TTC-stained cross-sections of a sham-operated (Sham-OP, left) and a cryoinfarcted (Cryo-MI, right) rat heart 6 hours after surgery. Transmural cryoinfarcted myocardium emerges as brown tissue with a gray-white border zone (right). Scale bar: 5 mm. (B) Representative mid-ventricular cross sections of a sham-operated (left) and cryoinfarcted (right) rat heart 12 weeks after surgery. Scale bar: 1 mm. (C) Representative images of a freshly isolated LV cardiomyocyte from a nonfailing sham-operated (NFC, left) and cryoinfarcted failing heart (FC, right) 12 weeks after surgery. Note the marked increase in end-diastolic length in the FC. Scale bar: 25 μm.
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