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

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• 作者：Julia O. Reynolds^a ; ^b ; ¹ ; Ann P. Quick^a ; ^b ; ¹ ; Qiongling Wang^a ; ^b ; ¹ ; David L. Beavers^a ; ^c ; Leonne E. Philippen^a ; ^b ; Jordan Showell^a ; ^b ; Giselle Barreto-Torres^a ; ^b ; Donna J. Thuerauf^f ; Shirin Doroudgar^g ; ^h ; Christopher C. Glembotski^f ; Xander H.T. Wehrens^a ; ^b ; ^d ; ^e ; ^{wehrens@bcm.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Calcium ; Cardiomyopathy ; Heart failure ; Junctophilin ; Gene therapy ; T-tubule
• 刊名：International Journal of Cardiology
• 出版年：2016
• 出版时间：15 December 2016
• 年：2016
• 卷：225
• 期：Complete
• 页码：371-380
• 全文大小：1439 K

文摘

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.