Junctophilin-2 gene therapy rescues heart failure by normalizing RyR2-mediated Ca 2 + release

• Published in: International journal of cardiology Vol. 225; p. 371
• Main Authors: Reynolds, Julia O, Quick, Ann P, Wang, Qiongling, Beavers, David L, Philippen, Leonne E, Showell, Jordan, Barreto-Torres, Giselle, Theurauf, Donna J, Doroudgar, Shirin, Glembotski, Christopher C, Wehrens, Xander H.T
• Format: Journal Article
• Language: English
• Published: Netherlands 15-12-2016
• Subjects: Adenoviridae - genetics; Animals; Calcium Signaling - drug effects; Calcium Signaling - physiology; Cardiovascular; Cells, Cultured; Genetic Therapy - methods; Genetic Vectors - administration & dosage; Genetic Vectors - genetics; Heart Failure - diagnostic imaging; Heart Failure - metabolism; Heart Failure - therapy; Male; Membrane Proteins - biosynthesis; Membrane Proteins - genetics; Mice; Mice, Inbred C57BL; Muscle Proteins - biosynthesis; Muscle Proteins - genetics; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Ryanodine Receptor Calcium Release Channel - physiology; heart failure; gene therapy; T-tubule; Calcium; junctophilin; cardiomyopathy; Heart failure; Junctophilin; Gene therapy; Cardiomyopathy
• ISSN: 0167-5273; 1874-1754
• DOI: 10.1016/j.ijcard.2016.10.021

Abstract Background Junctophilin-2 (JPH2) is the primary structural protein for coupling of transverse (T)-tubule associated cardiac L-type Ca channels and type-2 ryanodine receptors on the sarcoplasmic reticulum within junctional membrane complexes 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.