title: Junctophilin-2 gene therapy rescues heart failure by normalizing RyR2-mediated Ca2+release.
abstract: BACKGROUND
  Junctophilin-2 (JPH2) is the primary structural protein for the coupling of transverse (T)-tubule associated cardiac L-type Ca channels and type-2 ryanodine receptors on the sarcoplasmic reticulum within junctional membrane complexes (JMCs) in cardiomyocytes. Effective signaling between these channels ensures adequate Ca-induced Ca release required for normal cardiac contractility. Disruption of JMC subcellular domains, a common feature of failing hearts, has been attributed to JPH2 downregulation. Here, we tested the hypothesis that adeno-associated virus type 9 (AAV9) mediated overexpression of JPH2 could halt the development of heart failure in a mouse model of transverse aortic constriction (TAC).
  
  
  RESULTS
  Following TAC, a progressive decrease in ejection fraction was paralleled by a progressive decrease of cardiac JPH2 levels. AAV9-mediated expression of JPH2 rescued cardiac contractility in mice subjected to TAC. AAV9-JPH2 also preserved T-tubule structure. Moreover, the Ca2+spark frequency was reduced and the Ca2+transient amplitude was increased in AAV9-JPH2 mice following TAC, consistent with JPH2-mediated normalization of SR Ca2+handling.
  
  
  CONCLUSIONS
  This study demonstrates that AAV9-mediated JPH2 gene therapy maintained cardiac function in mice with early stage heart failure. Moreover, restoration of JPH2 levels prevented loss of T-tubules and suppressed abnormal SR Ca2+leak associated with contractile failure following TAC. These findings suggest that targeting JPH2 might be an attractive therapeutic approach for treating pathological cardiac remodeling during heart failure.
authors.affiliation: Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX 77030, USA; Dept. of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Julia O
authors.initials: JO
authors.lastname: Reynolds
authors.affiliation: Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX 77030, USA; Dept. of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Ann P
authors.initials: AP
authors.lastname: Quick
authors.affiliation: Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX 77030, USA; Dept. of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Qiongling
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX 77030, USA; Translational Biology and Molecular Medicine Program, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Beavers
authors.affiliation: Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX 77030, USA; Dept. of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Leonne E
authors.initials: LE
authors.lastname: Philippen
authors.affiliation: Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX 77030, USA; Dept. of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Jordan
authors.initials: J
authors.lastname: Showell
authors.affiliation: Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX 77030, USA; Dept. of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Giselle
authors.initials: G
authors.lastname: Barreto-Torres
authors.affiliation: San Diego State University Heart Institute and Department of Biology, San Diego State University, San Diego, CA 92182, USA.
authors.forename: Donna J
authors.initials: DJ
authors.lastname: Thuerauf
authors.affiliation: Department of Cardiology, Angiology, and Pneumology, University Hospital Heidelberg, Innere Medizin III, Im Neuenheimer Feld 669, 69120, Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, 69120, Heidelberg, Germany.
authors.forename: Shirin
authors.initials: S
authors.lastname: Doroudgar
authors.affiliation: San Diego State University Heart Institute and Department of Biology, San Diego State University, San Diego, CA 92182, USA.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Glembotski
authors.affiliation: Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX 77030, USA; Dept. of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX 77030, USA; Dept. of Medicine/Cardiology, Baylor College of Medicine, Houston, TX 77030, USA; Dept. of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: wehrens@bcm.edu.
authors.forename: Xander H T
authors.initials: XH
authors.lastname: Wehrens
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000628:therapy*; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009124:Muscle Proteins / Q000096:biosynthesis* / Q000235:genetics; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000502:physiology*
chemical_list: D008565:Membrane Proteins; D009124:Muscle Proteins; D019837:Ryanodine Receptor Calcium Release Channel; C000589042:JP2 protein, mouse; C000592748:ryanodine receptor 2. mouse
keywords: Calcium; Cardiomyopathy; Gene therapy; Heart failure; Junctophilin; T-tubule