title: S100A1 gene therapy preserves in vivo cardiac function after myocardial infarction.
abstract: Myocardial infarction (MI) represents an enormous clinical challenge as loss of myocardium due to ischemic injury is associated with compromised left ventricular (LV) function often leading to acute cardiac decompensation or chronic heart failure. S100A1 was recently identified as a positive inotropic regulator of myocardial contractility in vitro and in vivo. Here, we explore the strategy of myocardial S100A1 gene therapy either at the time of, or 2 h after, MI to preserve global heart function. Rats underwent cryothermia-induced MI and in vivo intracoronary delivery of adenoviral transgenes (4 x 10(10) pfu). Animals received saline (MI), the S100A1 adenovirus (MI/AdS100A1), a control adenovirus (MI/AdGFP), or a sham operation. S100A1 gene delivery preserved global in vivo LV function 1 week after MI. Preservation of LV function was due mainly to S100A1-mediated gain of contractility of the remaining, viable myocardium since contractile parameters and Ca(2+) transients of isolated MI/AdS100A1 myocytes were significantly enhanced compared to myocytes isolated from both MI/AdGFP and sham groups. Moreover, S100A1 gene therapy preserved the cardiac beta-adrenergic inotropic reserve, which was associated with the attenuation of GRK2 up-regulation. Also, S100A1 overexpression reduced cardiac hypertrophy 1 week post-MI. Overall, our data indicate that S100A1 gene therapy provides a potential novel treatment strategy to maintain contractile performance of the post-MI heart.
authors.affiliation: Medizinische Universitätsklinik und Poliklinik III, Otto Meyerhof Zentrum, Universität zu Heidelberg, INF 350, 69115 Heidelberg, Germany.
authors.forename: Sven T
authors.initials: ST
authors.lastname: Pleger
authors.forename: Andrew
authors.initials: A
authors.lastname: Remppis
authors.forename: Beatrix
authors.initials: B
authors.lastname: Heidt
authors.forename: Mirko
authors.initials: M
authors.lastname: Völkers
authors.forename: J Kurt
authors.initials: JK
authors.lastname: Chuprun
authors.forename: Matthew
authors.initials: M
authors.lastname: Kuhn
authors.forename: Rui-Hai
authors.initials: RH
authors.lastname: Zhou
authors.forename: Erhe
authors.initials: E
authors.lastname: Gao
authors.forename: Gabor
authors.initials: G
authors.lastname: Szabo
authors.forename: Dieter
authors.initials: D
authors.lastname: Weichenhan
authors.forename: Oliver J
authors.initials: OJ
authors.lastname: Müller
authors.forename: Andrea D
authors.initials: AD
authors.lastname: Eckhart
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Koch
authors.forename: Patrick
authors.initials: P
authors.lastname: Most
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics*; D003080:Cold Temperature; D004452:Echocardiography; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006352:Heart Ventricles / Q000473:pathology; D006439:Hemodynamics; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007511:Ischemia; D008297:Male; D015233:Models, Statistical; D009119:Muscle Contraction; D009203:Myocardial Infarction / Q000473:pathology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D012313:RNA / Q000378:metabolism; D051381:Rats; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D009418:S100 Proteins; D013997:Time Factors; D019076:Transgenes
chemical_list: D002135:Calcium-Binding Proteins; D011943:Receptors, Adrenergic, beta; D009418:S100 Proteins; C110294:S100A1 protein; D049452:Green Fluorescent Proteins; D012313:RNA; D002118:Calcium