PMID- 27760414 OWN - NLM STAT- MEDLINE DCOM- 20171025 LR - 20210112 IS - 1874-1754 (Electronic) IS - 0167-5273 (Print) IS - 0167-5273 (Linking) VI - 225 DP - 2016 Dec 15 TI - Junctophilin-2 gene therapy rescues heart failure by normalizing RyR2-mediated Ca(2+) release. PG - 371-380 LID - S0167-5273(16)32855-8 [pii] LID - 10.1016/j.ijcard.2016.10.021 [doi] AB - 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). METHODS AND 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 Ca(2+) spark frequency was reduced and the Ca(2+) transient amplitude was increased in AAV9-JPH2 mice following TAC, consistent with JPH2-mediated normalization of SR Ca(2+) 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 Ca(2+) 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. CI - Copyright (c) 2016 Elsevier Ireland Ltd. All rights reserved. FAU - Reynolds, Julia O AU - Reynolds JO AD - Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX 77030, USA; Dept. of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX 77030, USA. FAU - Quick, Ann P AU - Quick AP AD - Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX 77030, USA; Dept. of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX 77030, USA. FAU - Wang, Qiongling AU - Wang Q AD - Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX 77030, USA; Dept. of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX 77030, USA. FAU - Beavers, David L AU - Beavers DL AD - 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. FAU - Philippen, Leonne E AU - Philippen LE AD - Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX 77030, USA; Dept. of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX 77030, USA. FAU - Showell, Jordan AU - Showell J AD - Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX 77030, USA; Dept. of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX 77030, USA. FAU - Barreto-Torres, Giselle AU - Barreto-Torres G AD - Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX 77030, USA; Dept. of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX 77030, USA. FAU - Thuerauf, Donna J AU - Thuerauf DJ AD - San Diego State University Heart Institute and Department of Biology, San Diego State University, San Diego, CA 92182, USA. FAU - Doroudgar, Shirin AU - Doroudgar S AD - 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. FAU - Glembotski, Christopher C AU - Glembotski CC AD - San Diego State University Heart Institute and Department of Biology, San Diego State University, San Diego, CA 92182, USA. FAU - Wehrens, Xander H T AU - Wehrens XH AD - 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. LA - eng GR - R01 HL075573/HL/NHLBI NIH HHS/United States GR - R01 HL127439/HL/NHLBI NIH HHS/United States GR - T32 HL007676/HL/NHLBI NIH HHS/United States GR - R41 HL129570/HL/NHLBI NIH HHS/United States GR - R01 HL089598/HL/NHLBI NIH HHS/United States GR - U54 HG006348/HG/NHGRI NIH HHS/United States GR - P01 HL085577/HL/NHLBI NIH HHS/United States GR - R25 GM069234/GM/NIGMS NIH HHS/United States GR - R01 HL117641/HL/NHLBI NIH HHS/United States GR - R01 HL104535/HL/NHLBI NIH HHS/United States GR - R01 HL091947/HL/NHLBI NIH HHS/United States PT - Journal Article DEP - 20161008 PL - Netherlands TA - Int J Cardiol JT - International journal of cardiology JID - 8200291 RN - 0 (Membrane Proteins) RN - 0 (Muscle Proteins) RN - 0 (Ryanodine Receptor Calcium Release Channel) RN - 0 (junctophilin-2 protein, mouse) RN - 0 (ryanodine receptor 2. mouse) SB - IM MH - Adenoviridae/genetics MH - Animals MH - Calcium Signaling/drug effects/*physiology MH - Cells, Cultured MH - Genetic Therapy/*methods MH - Genetic Vectors/administration & dosage/genetics MH - Heart Failure/diagnostic imaging/*metabolism/*therapy MH - Male MH - Membrane Proteins/*biosynthesis/genetics MH - Mice MH - Mice, Inbred C57BL MH - Muscle Proteins/*biosynthesis/genetics MH - Myocytes, Cardiac/drug effects/metabolism MH - Ryanodine Receptor Calcium Release Channel/*physiology PMC - PMC5101129 MID - NIHMS823603 OTO - NOTNLM OT - Calcium OT - Cardiomyopathy OT - Gene therapy OT - Heart failure OT - Junctophilin OT - T-tubule COIS- 6. CONFLICT OF INTEREST None declared. EDAT- 2016/10/21 06:00 MHDA- 2017/10/27 06:00 PMCR- 2017/12/15 CRDT- 2016/10/21 06:00 PHST- 2016/08/24 00:00 [received] PHST- 2016/10/05 00:00 [revised] PHST- 2016/10/07 00:00 [accepted] PHST- 2016/10/21 06:00 [pubmed] PHST- 2017/10/27 06:00 [medline] PHST- 2016/10/21 06:00 [entrez] PHST- 2017/12/15 00:00 [pmc-release] AID - S0167-5273(16)32855-8 [pii] AID - 10.1016/j.ijcard.2016.10.021 [doi] PST - ppublish SO - Int J Cardiol. 2016 Dec 15;225:371-380. doi: 10.1016/j.ijcard.2016.10.021. Epub 2016 Oct 8.