title: S100A1 genetically targeted therapy reverses dysfunction of human failing cardiomyocytes.
abstract: OBJECTIVE
  This study investigated the hypothesis whether S100A1 gene therapy can improve pathological key features in human failing ventricular cardiomyocytes (HFCMs).
  
  
  BACKGROUND
  Depletion of the Ca²⁺-sensor protein S100A1 drives deterioration of cardiac performance toward heart failure (HF) in experimental animal models. Targeted repair of this molecular defect by cardiac-specific S100A1 gene therapy rescued cardiac performance, raising the immanent question of its effects in human failing myocardium.
  
  
  METHODS
  Enzymatically isolated HFCMs from hearts with severe systolic HF were subjected to S100A1 and control adenoviral gene transfer and contractile performance, calcium handling, signaling, and energy homeostasis were analyzed by video-edge-detection, FURA2-based epifluorescent microscopy, phosphorylation site-specific antibodies, and mitochondrial assays, respectively.
  
  
  RESULTS
  Genetically targeted therapy employing the human S100A1 cDNA normalized decreased S100A1 protein levels in HFCMs, reversed both contractile dysfunction and negative force-frequency relationship, and improved contractile reserve under beta-adrenergic receptor (β-AR) stimulation independent of cAMP-dependent (PKA) and calmodulin-dependent (CaMKII) kinase activity. S100A1 reversed underlying Ca²⁺ handling abnormalities basally and under β-AR stimulation shown by improved SR Ca²⁺ handling, intracellular Ca²⁺ transients, diastolic Ca²⁺ overload, and diminished susceptibility to arrhythmogenic SR Ca²⁺ leak, respectively. Moreover, S100A1 ameliorated compromised mitochondrial function and restored the phosphocreatine/adenosine-triphosphate ratio.
  
  
  CONCLUSIONS
  Our results demonstrate for the first time the therapeutic efficacy of genetically reconstituted S100A1 protein levels in HFCMs by reversing pathophysiological features that characterize human failing myocardium. Our findings close a gap in our understanding of S100A1's effects in human cardiomyocytes and strengthen the rationale for future molecular-guided therapy of human HF.
authors.affiliation: Department of Cardiac and Vascular Surgery, University Hospital Berne, Bern, Switzerland.
authors.forename: Henriette
authors.initials: H
authors.lastname: Brinks
authors.forename: David
authors.initials: D
authors.lastname: Rohde
authors.forename: Mirko
authors.initials: M
authors.lastname: Voelkers
authors.forename: Gang
authors.initials: G
authors.lastname: Qiu
authors.forename: Sven T
authors.initials: ST
authors.lastname: Pleger
authors.forename: Nicole
authors.initials: N
authors.lastname: Herzog
authors.forename: Joseph
authors.initials: J
authors.lastname: Rabinowitz
authors.forename: Arjang
authors.initials: A
authors.lastname: Ruhparwar
authors.forename: Scott
authors.initials: S
authors.lastname: Silvestry
authors.forename: Carolin
authors.initials: C
authors.lastname: Lerchenmüller
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Mather
authors.forename: Andrea D
authors.initials: AD
authors.lastname: Eckhart
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.forename: Thierry
authors.initials: T
authors.lastname: Carrel
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Koch
authors.forename: Patrick
authors.initials: P
authors.lastname: Most
mesh_terms: D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D015316:Genetic Therapy / Q000379:methods*; D006333:Heart Failure / Q000235:genetics* / Q000473:pathology* / Q000628:therapy; D006801:Humans; D032383:Myocytes, Cardiac / Q000473:pathology* / Q000502:physiology*; D009418:S100 Proteins / Q000096:biosynthesis* / Q000235:genetics*
chemical_list: D009418:S100 Proteins; C110294:S100A1 protein; D002118:Calcium