Junctophilin-2 gene therapy rescues heart failure by normalizing RyR2-mediated Ca2 + release

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

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)371-380
Number of pages10
JournalInternational Journal of Cardiology
Volume225
DOIs
StatePublished - Dec 15 2016
Externally publishedYes

Keywords

  • Calcium
  • Cardiomyopathy
  • Gene therapy
  • Heart failure
  • Junctophilin
  • T-tubule

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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