Junctophilin-2 gene therapy rescues heart failure by normalizing RyR2-mediated Ca2+ release
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 channe...
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| Main Authors: | , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
8 October 2016
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| In: |
International journal of cardiology
Year: 2016, Volume: 225, Pages: 371-380 |
| ISSN: | 1874-1754 |
| DOI: | 10.1016/j.ijcard.2016.10.021 |
| Online Access: | Verlag, Volltext: http://dx.doi.org/10.1016/j.ijcard.2016.10.021 Verlag, Volltext: http://www.sciencedirect.com/science/article/pii/S0167527316328558 
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| Author Notes: | Julia O. Reynolds, Ann P. Quick, Qiongling Wang, David L. Beavers, Leonne E. Philippen, Jordan Showell, Giselle Barreto-Torres, Donna J. Thuerauf, Shirin Doroudgar, Christopher C. Glembotski, Xander H.T. Wehrens |
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| 520 | |a 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). 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. 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. | ||
| 650 | 4 | |a Calcium | |
| 650 | 4 | |a Cardiomyopathy | |
| 650 | 4 | |a Gene therapy | |
| 650 | 4 | |a Heart failure | |
| 650 | 4 | |a Junctophilin | |
| 650 | 4 | |a T-tubule | |
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