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

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 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.

Colchicine Depolymerizes Microtubules, Increases Junctophilin‐2, and Improves Right Ventricular Function in Experimental Pulmonary Arterial Hypertension

“…We propose that increases in JPH2 and improvements in t‐tubule morphology mediate the augmented RV function, which is further supported by the significant relationships between JPH2 and RV function (Figure 5). These results agree with several studies showing that reduced levels of JPH2 are associated with left ventricular dysfunction in animal models36, 37, 38, 39, 40 and human disease states15, 41 and that increased expression of JPH2, achieved via transgenic overexpression,19 antagonism of miR‐24,42 viral‐mediated overexpression,20 or inhibition of calpain proteases,43 improves cardiac function in animal models of LV dysfunction. Thus, increased JPH2 likely mediates the improved RV‐PA coupling in MCT‐colchicine rats.…”

“…JPH2 is a protein that is essential for life17 because of its critical roles in maintaining cardiomyocyte t‐tubule structure and regulating calcium handling by gating the ryanodine receptor 18. Moreover, transgenic19 and virally mediated overexpression20 of JPH2 augments LV function in mice with LV dysfunction caused by aortic banding. Although there is strong evidence that JPH2 plays a significant role in LV dysfunction, little is known about the role of microtubule structure and JPH2 expression in RV dysfunction associated with PAH.…”

Caveolin 3‐dependent loss of t‐tubular ICa during hypertrophy and heart failure in mice

“…To investigate whether the graded changes in t‐tubule structure observed in HTY and HF myocytes could be attributable to graded changes in expression of Jph2, Bin1 and/or Cav3, all of which have been implicated in t‐tubule formation and maintenance (Caldwell et al., ; Ziman, Gómez‐Viquez, Bloch, & Lederer, ) and have been reported to change in HF (Frisk et al., ; Reynolds et al., ), we investigated the expression of these proteins in each group. Representative Western blots and mean data are shown in Figure .…”

Remodeling of the transverse tubular system after myocardial infarction in rabbit correlates with local fibrosis: A potential role of biomechanics

“…Junctophilin knockdown caused impaired t-tubule maturation and cardiac hypertrophy in mice (Landstrom et al, 2011; Reynolds et al, 2013). Also, junctophilin overexpression was suggested to normalize excitation-contraction coupling and cardiac function in murine heart failure models (Guo et al, 2014; Reynolds et al, 2016). However, it is still unclear if reduced junctophilin expression leads to t-system remodeling or, vice versa, the loss of t-tubules causes reduced junctophilin protein levels.…”