Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • Aging (Jul 2022)
    • Next-Generation Sequencing in Medicine (Jun 2022)
    • New Therapeutic Targets in Cardiovascular Diseases (Mar 2022)
    • Immunometabolism (Jan 2022)
    • Circadian Rhythm (Oct 2021)
    • Gut-Brain Axis (Jul 2021)
    • Tumor Microenvironment (Mar 2021)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • In-Press Preview
  • Commentaries
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
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.
View: Text | PDF
Article Cardiology

Cardiac adenoviral S100A1 gene delivery rescues failing myocardium

  • Text
  • PDF
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

×

Figure 3

Options: View larger image (or click on image) Download as PowerPoint
S100A1-mediated rescue of contractile dysfunction in vitro. (A) Efficien...
S100A1-mediated rescue of contractile dysfunction in vitro. (A) Efficiency of adenovirus-mediated gene transfer in FCs. Representative transmission (left) and GFP emission images (right) from FCs 24 hours after adenoviral infection. Upper left: FCs-AdGFP transmission; upper right: FCs-AdGFP, 510-nm emission; lower left: FCs-AdS100A1 transmission; lower right: FCs-AdS100A1, 510-nm emission. Scale bar: 100 μm. (B) Restoration of S100A1 protein levels in FCs 24 hours after S100A1 gene transfer. Representative results of Western blots for SERCA2, NCX, CSQ, cardiac actin, GFP, PLB, and S100A1 from homogenates both of untreated NFCs and FCs and AdGFP- and AdS100A1-transfected FCs. Note that GFP is only expressed in adenovirus-treated failing cells. Data are shown from 2 different representative preparations (animals 82 and 93). (C) Rescue of contractile function in FCs after adenoviral S100A1 gene transfer. Original tracings of FS (shown as downward deflection) from a representative NFC, FC, FC-AdGFP, and FC-AdS100A1. (D) Normalization of FS (upper panel), rate of cellular shortening (_dl/dt; μm/ms; middle panel), and rate of cellular relengthening (+dl/dt; μm/ms; lower panel) in FCs after S100A1 gene addition (n = 40 cells from 4 different preparations in each group; *P < 0.01 compared with NFCs; **P < 0.01 compared with FCs and FCs-AdGFP); P = NS, NFCs vs. FCs-AdS100A1. Data are presented as mean ± SEM.

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts