Effects of induced Na+/Ca2+ exchanger overexpression on the spatial distribution of L-type Ca2+ channels and junctophilin-2 in pressure-overloaded hearts.
Effects of induced Na+/Ca2+ exchanger overexpression on the spatial distribution of L-type Ca2+ channels and junctophilin-2 in pressure-overloaded hearts.
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DOI：
10.1016/j.bbrc.2016.10.090
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发表时间：
2016-11
影响因子：
3.1
通讯作者：
Y. Ujihara;S. Mohri;Y. Katanosaka
中科院分区：
文献类型：
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作者：
Y. Ujihara;S. Mohri;Y. Katanosaka
Na+/Ca2+交换器 1 (NCX1) 是心肌细胞中重要的 Ca2+ 流出系统。尽管 NCX1 分布于整个肌膜，但 NCX1 的一个亚群定位于横管 (T)。越来越多的证据表明，T 管紊乱是导致肥大转变为心力衰竭 (HF) 的因果事件。然而，详细的分子机制尚未阐明。此前，我们发现在压力超负荷的心脏中诱导 NCX1 表达可减弱有缺陷的兴奋-收缩耦合和心力衰竭进展。在这里，我们检查了诱导的 NCX1 过表达对压力超负荷心脏中 L 型 Ca2+ 通道 (LTCC) 和 junctophilin-2 (JP2) 空间分布的影响，JP2 是一种连接 T 管和肌浆网膜的结构蛋白。定量分析表明，主动脉横缩术（TAC）术后8周，NCX1定位的规律性显着降低；然而，此时 T 管组织以及 LTCC 和 JP2 免疫荧光信号的规律性保持不变。这些观察结果表明，NCX1 从 T 管区域释放发生在 T 管解体和 LTCC 和 JP2 错误定位发生之前。此外，TAC后8周诱导的NCX1过度表达不仅恢复了NCX1的规律性，而且还防止了TAC后16周时LTCC和JP2规律性的下降。这些结果表明，在压力超载的情况下，NCX1 可能在 T 管中 LTCC 和 JP2 的正确空间分布中发挥重要作用。
The Na+/Ca2+exchanger 1 (NCX1) is an essential Ca2+efflux system in cardiomyocytes. Although NCX1 is distributed throughout the sarcolemma, a subpopulation of NCX1 is localized to transverse (T)-tubules. There is growing evidence that T-tubule disorganization is a causal event that shifts the transition from hypertrophy to heart failure (HF). However, the detailed molecular mechanisms have not been clarified. Previously, we showed that induced NCX1 expression in pressure-overloaded hearts attenuates defective excitation-contraction coupling and HF progression. Here, we examined the effects of induced NCX1 overexpression on the spatial distribution of L-type Ca2+channels (LTCCs) and junctophilin-2 (JP2), a structural protein that connects the T-tubule and sarcoplasmic reticulum membrane, in pressure-overloaded hearts. Quantitative analysis showed that the regularity of NCX1 localization was significantly decreased at 8 weeks after transverse aortic constriction (TAC)-surgery; however, T-tubule organization and the regularities of LTCC and JP2 immunofluorescent signals were maintained at this time point. These observations demonstrated that release of NCX1 from the T-tubule area occurred before the onset of T-tubule disorganization and LTCC and JP2 mislocalization. Moreover, induced NCX1 overexpression at 8 weeks post-TAC not only recovered NCX1 regularity but also prevented the decrease in LTCC and JP2 regularities at 16 weeks post-TAC. These results suggested that NCX1 may play an important role in the proper spatial distribution of LTCC and JP2 in T-tubules in the context of pressure-overloading.