Stromal interaction molecule 1 is essential for normal cardiac homeostasis through modulation of ER and mitochondrial function
Stromal interaction molecule 1 is essential for normal cardiac homeostasis through modulation of ER and mitochondrial function
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DOI：
10.1152/ajpheart.00075.2014
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发表时间：
2014-04-01
影响因子：
4.8
通讯作者：
Chatham, John C.
中科院分区：
文献类型：
--
作者：
Collins, Helen E.;He, Lan;Chatham, John C.
内质网（ER） Ca2+传感器基质相互作用分子1 （STIM1）已被认为是存储依赖性和存储非依赖性Ca2+进入途径和内质网结构维持的关键介质。STIM1存在于胚胎、新生儿和成人心肌细胞中，并与肥厚信号传导密切相关；然而，STIM1在成人心脏中的生理作用尚不清楚。因此，我们开发了一种新的心肌细胞限制性STIM1敲除（(cr)STIM1- ko）小鼠。在从（cr）STIM1- ko小鼠分离的心肌细胞中，STIM1的表达减少了92%，而相关的储存操作的Ca2+进入蛋白、STIM2和Orai1的表达没有变化。免疫印迹分析显示，（cr）STIM1-KO心脏从12周开始表现出内质网应激增加，转录因子C/EBP同源蛋白（CHOP）水平升高，这是内质网应激的终端标志物之一。透射电镜显示（cr）STIM1-KO心脏内质网扩张，线粒体解体，小线粒体数量增加，这与线粒体裂变增加有关。通过一系列超声心动图和组织学分析，我们观察到（cr）STIM1-KO小鼠的心功能从20周龄开始逐渐下降，这与36周龄时明显的左心室扩张有关。此外，我们在（cr）STIM1-KO小鼠中观察到炎症浸润的存在和心脏纤维化的证据，从20周开始，到36周逐渐恶化。这些数据首次证明STIM1在成人心脏正常心功能中起重要作用，这可能对ER和线粒体功能的调节很重要。
The endoplasmic reticulum (ER) Ca2+ sensor stromal interaction molecule 1 (STIM1) has been implicated as a key mediator of store-dependent and store-independent Ca2+ entry pathways and maintenance of ER structure. STIM1 is present in embryonic, neonatal, and adult cardiomyocytes and has been strongly implicated in hypertrophic signaling; however, the physiological role of STIM1 in the adult heart remains unknown. We, therefore, developed a novel cardiomyocyte-restricted STIM1 knockout ((cr)STIM1-KO) mouse. In cardiomyocytes isolated from (cr)STIM1-KO mice, STIM1 expression was reduced by similar to 92% with no change in the expression of related store-operated Ca2+ entry proteins, STIM2, and Orai1. Immunoblot analyses revealed that (cr)STIM1-KO hearts exhibited increased ER stress from 12 wk, as indicated by increased levels of the transcription factor C/EBP homologous protein (CHOP), one of the terminal markers of ER stress. Transmission electron microscopy revealed ER dilatation, mitochondrial disorganization, and increased numbers of smaller mitochondria in (cr)STIM1-KO hearts, which was associated with increased mitochondrial fission. Using serial echocardiography and histological analyses, we observed a progressive decline in cardiac function in (cr)STIM1-KO mice, starting at 20 wk of age, which was associated with marked left ventricular dilatation by 36 wk. In addition, we observed the presence of an inflammatory infiltrate and evidence of cardiac fibrosis from 20 wk in (cr)STIM1-KO mice, which progressively worsened by 36 wk. These data demonstrate for the first time that STIM1 plays an essential role in normal cardiac function in the adult heart, which may be important for the regulation of ER and mitochondrial function.