STIM1-dependent Ca(2+) microdomains are required for myofilament remodeling and signaling in the heart.
STIM1-dependent Ca(2+) microdomains are required for myofilament remodeling and signaling in the heart.
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DOI：
10.1038/srep25372
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发表时间：
2016-05-06
影响因子：
4.6
通讯作者：
Mancarella S
中科院分区：
文献类型：
--
作者：
Parks C;Alam MA;Sullivan R;Mancarella S
在不可兴奋的细胞中，基质相互作用分子1(STIM1)是产生钙信号的关键元件，钙信号导致基因表达、迁移和细胞增殖。越来越多的文献表明，STIM1在病理性心肌肥厚的发生发展中起着关键作用。然而，心脏中涉及STIM依赖的钙信号的确切机制尚不清楚。在此，我们研究了心肌细胞中STIM1相关的钙信号及其与病理性心脏重构的关系。我们发现，可诱导的、心脏受限的、消融STIM1的小鼠表现出左心室收缩能力降低，这一点得到了单细胞收缩能力受损的证实。STIM1依赖的钙信号的空间特性决定了调控肌丝重构和激活空间分离的促肥大因子的限制性钙微域。事实上，缺乏STIM1的小鼠在压力超负荷诱导的心肌肥厚反应中表现出较少的不良结构重构。这些结果突显了STIM1依赖的钙微域如何对细胞内钙稳态、细胞骨架重塑和细胞信号产生重大影响，即使在存在兴奋-收缩耦合的情况下也是如此。
In non-excitable cells stromal interaction molecule 1 (STIM1) is a key element in the generation of Ca2+ signals that lead to gene expression, migration and cell proliferation. A growing body of literature suggests that STIM1 plays a key role in the development of pathological cardiac hypertrophy. However, the precise mechanisms involving STIM-dependent Ca2+ signaling in the heart are not clearly established. Here, we have investigated the STIM1-associated Ca2+ signals in cardiomyocytes and their relevance to pathological cardiac remodeling. We show that mice with inducible, cardiac-restricted, ablation of STIM1 exhibited left ventricular reduced contractility, which was corroborated by impaired single cell contractility. The spatial properties of STIM1-dependent Ca2+ signals determine restricted Ca2+ microdomains that regulate myofilament remodeling and activate spatially segregated pro-hypertrophic factors. Indeed, mice lacking STIM1 showed less adverse structural remodeling in response to pressure overload-induced cardiac hypertrophy. These results highlight how STIM1-dependent Ca2+ microdomains have a major impact on intracellular Ca2+ homeostasis, cytoskeletal remodeling and cellular signaling, even when excitation-contraction coupling is present.