Julia O Reynolds1, Ann P Quick1, Qiongling Wang1, David L Beavers2, Leonne E Philippen1, Jordan Showell1, Giselle Barreto-Torres1, Donna J Thuerauf3, Shirin Doroudgar4, Christopher C Glembotski3, Xander H T Wehrens5. 1. Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX 77030, USA; Dept. of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX 77030, USA. 2. 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. 3. San Diego State University Heart Institute and Department of Biology, San Diego State University, San Diego, CA 92182, USA. 4. 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. 5. 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.
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). 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 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.
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 Ca2+ spark frequency was reduced and the Ca2+ transient amplitude was increased in AAV9-JPH2mice 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: Mariell Jessup; William T Abraham; Donald E Casey; Arthur M Feldman; Gary S Francis; Theodore G Ganiats; Marvin A Konstam; Donna M Mancini; Peter S Rahko; Marc A Silver; Lynne Warner Stevenson; Clyde W Yancy Journal: Circulation Date: 2009-03-26 Impact factor: 29.690
Authors: Ralph J van Oort; Jonathan L Respress; Na Li; Corey Reynolds; Angela C De Almeida; Darlene G Skapura; Leon J De Windt; Xander H T Wehrens Journal: Hypertension Date: 2010-02-15 Impact factor: 10.190
Authors: Oliver J Müller; Barbara Leuchs; Sven T Pleger; Dirk Grimm; Wolfgang-M Franz; Hugo A Katus; Jürgen A Kleinschmidt Journal: Cardiovasc Res Date: 2006-01-31 Impact factor: 10.787
Authors: Frank B Sachse; Natalia S Torres; Eleonora Savio-Galimberti; Takeshi Aiba; David A Kass; Gordon F Tomaselli; John H Bridge Journal: Circ Res Date: 2012-01-17 Impact factor: 17.367
Authors: Lawrence T Bish; Kevin Morine; Meg M Sleeper; Julio Sanmiguel; Di Wu; Guangping Gao; James M Wilson; H Lee Sweeney Journal: Hum Gene Ther Date: 2008-12 Impact factor: 5.695
Authors: Qiongling Wang; Ann P Quick; Shuyi Cao; Julia Reynolds; David Y Chiang; David Beavers; Na Li; Guoliang Wang; George G Rodney; Mark E Anderson; Xander H T Wehrens Journal: Circ Arrhythm Electrophysiol Date: 2018-04
Authors: Tanner O Monroe; Matthew C Hill; Yuka Morikawa; John P Leach; Todd Heallen; Shuyi Cao; Peter H L Krijger; Wouter de Laat; Xander H T Wehrens; George G Rodney; James F Martin Journal: Dev Cell Date: 2019-02-14 Impact factor: 12.270
Authors: David P Ferguson; Tanner O Monroe; Celia Pena Heredia; Ryan Fleischmann; George G Rodney; George E Taffet; Marta L Fiorotto Journal: J Physiol Date: 2019-03-03 Impact factor: 5.182
Authors: Gaelle Auguste; Priyatansh Gurha; Raffaella Lombardi; Cristian Coarfa; James T Willerson; Ali J Marian Journal: Circ Res Date: 2018-01-09 Impact factor: 17.367
Authors: Sören Brandenburg; Jan Pawlowitz; Benjamin Eikenbusch; Jonas Peper; Tobias Kohl; Gyuzel Y Mitronova; Samuel Sossalla; Gerd Hasenfuss; Xander Ht Wehrens; Peter Kohl; Eva A Rog-Zielinska; Stephan E Lehnart Journal: JCI Insight Date: 2019-06-20
Authors: Yankun Lyu; Vipin K Verma; Stavros G Drakos; Frank B Sachse; Younjee Lee; Iosif Taleb; Rachit Badolia; Thirupura S Shankar; Christos P Kyriakopoulos; Craig H Selzman; William Caine; Rami Alharethi; Sutip Navankasattusas; Thomas Seidel Journal: NPJ Aging Mech Dis Date: 2021-05-28