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
Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX 77030, USA; Dept. of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX 77030, USA; Translational Biology and Molecular Medicine Program, Baylor College of Medicine, Houston, TX 77030, USA.
Int J Cardiol. 2016 Dec 15;225:371-380. doi: 10.1016/j.ijcard.2016.10.021. Epub 2016 Oct 8.
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).
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 spark frequency was reduced and the Ca transient amplitude was increased in AAV9-JPH2 mice following TAC, consistent with JPH2-mediated normalization of SR Ca handling.
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 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.
连接蛋白2（JPH2）是心肌细胞连接膜复合物（JMCs）中横管（T管）相关的心脏L型钙通道与肌浆网上的2型兰尼碱受体偶联的主要结构蛋白。这些通道之间的有效信号传导可确保正常心脏收缩所需的足够的钙诱导钙释放。JMC亚细胞结构域的破坏是衰竭心脏的一个常见特征，这归因于JPH2的下调。在此，我们测试了以下假设：9型腺相关病毒（AAV9）介导的JPH2过表达可阻止横主动脉缩窄（TAC）小鼠模型中心力衰竭的发展。
TAC后，射血分数逐渐下降，同时心脏JPH2水平也逐渐下降。AAV9介导的JPH2表达挽救了TAC小鼠的心脏收缩功能。AAV9-JPH2还保留了T管结构。此外，TAC后AAV9-JPH2小鼠的钙火花频率降低，钙瞬变幅度增加，这与JPH2介导的肌浆网钙处理正常化一致。
本研究表明，AAV9介导的JPH2基因治疗可维持早期心力衰竭小鼠的心脏功能。此外，JPH2水平的恢复可防止T管丢失，并抑制TAC后与收缩功能衰竭相关的异常肌浆网钙泄漏。这些发现表明，靶向JPH2可能是治疗心力衰竭期间病理性心脏重塑的一种有吸引力的治疗方法。
