Junctophilin-2 gene therapy rescues heart failure by normalizing RyR2-mediated Ca2 + release. (15th December 2016)

• Record Type: Journal Article
• Authors: Reynolds, Julia O.; Quick, Ann P.; Wang, Qiongling; Beavers, David L.; Philippen, Leonne E.; Showell, Jordan; Barreto-Torres, Giselle; Thuerauf, Donna J.; Doroudgar, Shirin; Glembotski, Christopher C.; Wehrens, Xander H.T.
• Is Part Of: International journal of cardiology. Volume 225(2016)
• Page Start: 371
• Page End: 380
• Publication Date: 2016-12-15
• Subjects: Calcium -- Cardiomyopathy -- Heart failure -- Junctophilin -- Gene therapy -- T-tubule; Cardiology -- Periodicals; Electronic journals; 616.12
• DOI: 10.1016/j.ijcard.2016.10.021
• Languages: English
• ISSNs: 0167-5273

Abstract

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 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.