title: 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.affiliation: Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA. patrick.most@jefferson.edu
authors.forename: Patrick
authors.initials: P
authors.lastname: Most
authors.forename: Sven T
authors.initials: ST
authors.lastname: Pleger
authors.forename: Mirko
authors.initials: M
authors.lastname: Völkers
authors.forename: Beatrix
authors.initials: B
authors.lastname: Heidt
authors.forename: Melanie
authors.initials: M
authors.lastname: Boerries
authors.forename: Dieter
authors.initials: D
authors.lastname: Weichenhan
authors.forename: Eva
authors.initials: E
authors.lastname: Löffler
authors.forename: Paul M L
authors.initials: PM
authors.lastname: Janssen
authors.forename: Andrea D
authors.initials: AD
authors.lastname: Eckhart
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Martini
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Williams
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.forename: Andrew
authors.initials: A
authors.lastname: Remppis
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Koch
mesh_terms: D000256:Adenoviridae / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D002303:Cardiac Output, Low / Q000628:therapy*; D002522:Chlorocebus aethiops; D005260:Female; D018507:Gene Expression Regulation, Developmental; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006321:Heart / Q000033:anatomy & histology / Q000502:physiology*; D006439:Hemodynamics; D006801:Humans; D008297:Male; D009200:Myocardial Contraction; D009203:Myocardial Infarction / Q000473:pathology / Q000628:therapy; D009206:Myocardium / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D009418:S100 Proteins; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases
chemical_list: D002135:Calcium-Binding Proteins; D009418:S100 Proteins; C110294:S100A1 protein; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000252:Calcium-Transporting ATPases; D002118:Calcium