Calpain-dependent cleavage of junctophilin-2 and T-tubule remodeling in a mouse model of reversible heart failure.
Calpain-dependent cleavage of junctophilin-2 and T-tubule remodeling in a mouse model of reversible heart failure.
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DOI：
10.1161/jaha.113.000527
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发表时间：
2014-06-23
影响因子：
5.4
通讯作者：
Lin RZ
中科院分区：
文献类型：
--
作者：
Wu CY;Chen B;Jiang YP;Jia Z;Martin DW;Liu S;Entcheva E;Song LS;Lin RZ
高度组织化的横小管（T -小管）网络对于有效的Ca2+诱导的Ca2+释放和心室肌细胞的同步收缩是必要的。越来越多的证据表明，结膜亲素- 2 （JP - 2）下调引起的T小管重构在心力衰竭的进展中起着关键作用。然而，JP - 2失调的机制仍然不完全清楚。在这项研究中，使用了一种由心肌细胞中异源三聚体G蛋白Gαq条件激活驱动的可逆性心力衰竭小鼠模型。与野生型小鼠相比，激活g - αq的小鼠表现出T小管网络破坏和Ca2+处理缺陷，最终导致心力衰竭。g - αq/磷脂酶Cβ信号的激活增加了Ca2+依赖性蛋白酶calpain的活性，导致JP - 2的蛋白水解裂解。一个新的钙蛋白酶裂解片段JP‐2仅在心脏中检测到组成Gαq信号传导到磷脂酶Cβ。Gαq信号终止后，JP - 2蛋白水平正常化，T小管网络修复，Ca2+处理改善，心力衰竭逆转。用钙蛋白酶抑制剂治疗小鼠可防止Gαq依赖性JP - 2裂解、T小管破坏和心力衰竭的发生。心衰时T小管网络的破坏是一个可逆的过程。在该小鼠模型中，Gαq依赖性的钙蛋白酶激活和随后的JP - 2蛋白水解似乎是导致T小管重塑、Ca2+处理功能障碍和进展为心力衰竭的分子机制。
A highly organized transverse tubule (T‐tubule) network is necessary for efficient Ca2+‐induced Ca2+ release and synchronized contraction of ventricular myocytes. Increasing evidence suggests that T‐tubule remodeling due to junctophilin‐2 (JP‐2) downregulation plays a critical role in the progression of heart failure. However, the mechanisms underlying JP‐2 dysregulation remain incompletely understood. A mouse model of reversible heart failure that is driven by conditional activation of the heterotrimeric G protein Gαq in cardiac myocytes was used in this study. Mice with activated Gαq exhibited disruption of the T‐tubule network and defects in Ca2+ handling that culminated in heart failure compared with wild‐type mice. Activation of Gαq/phospholipase Cβ signaling increased the activity of the Ca2+‐dependent protease calpain, leading to the proteolytic cleavage of JP‐2. A novel calpain cleavage fragment of JP‐2 is detected only in hearts with constitutive Gαq signaling to phospholipase Cβ. Termination of the Gαq signal was followed by normalization of the JP‐2 protein level, repair of the T‐tubule network, improvements in Ca2+ handling, and reversal of heart failure. Treatment of mice with a calpain inhibitor prevented Gαq‐dependent JP‐2 cleavage, T‐tubule disruption, and the development of heart failure. Disruption of the T‐tubule network in heart failure is a reversible process. Gαq‐dependent activation of calpain and subsequent proteolysis of JP‐2 appear to be the molecular mechanism that leads to T‐tubule remodeling, Ca2+ handling dysfunction, and progression to heart failure in this mouse model.